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THE 


EVOLUTION  OF  DISEASE 


DISCUSSION   OF    THE    IMMUNE    REACTIONS   OCCURRING 
IN  INFECTIOUS  AND  NON-INFECTIOUS  DISEASES 

A  THEORY  OF  IMMUNITY,  OF  ANAPHYLAXIS 
AND  OF  ANTIANAPHYLAXIS 


BY 

PROF.  J.  DANYSZ 

CHEF  DE  SERVICE,  INS'm'UT  PASTEUR,    PARIS 


TRANSLATED   BY 

FRANCIS  M.  RACKEMANN,  M.D. 

ASSISTANT    IN   MEDICINE    IN   THE    HARVARD   MEDICAL   SCHOOL;    ASSISTANT   IN 
MEDICINE  IN  THE  MASSACHUSETTS  GENERAL  HOSPITAL,  BOSTON,  MASS. 


LEA  &  FEBIGER 

PHILADELPHIA   AND   NEW   YORK 
1921 


COPYBIGHT 

LEA  &  FEBIGER 

1921 


TRANSLATOR'S  NOTE 


In  translating  this  work  of  Professor  Danysz  from  French 
into  English,  an  attempt  has  been  made  to  preserve  carefully 
the  original  meaning.  The  original  work  contains  much 
repetition  arising  from  the  desire  to  emphasize  and  elucidate 
the  author's  theories  and  deductions  on  the  evolution  of 
disease:  the  translation  also  contains  repetition  but  the 
translator  has  taken  the  liberty  of  omitting  sentences,  para- 
graphs and,  in  certain  instances,  whole  sections,  in  order  to 
present  the  book  to  the  American  profession  in  a  more  read- 
able form.  In  particular,  the  case  reports  in  the  second 
section  of  the  second  part  have  been  greatly  shortened  and 
many  have  been  omitted. 

In  this  book  Professor  Danysz  has  traced  in  a  clear  and 
logical  manner  the  various  stages  in  the  development  of  acute 
infectious  diseases;  and  proceeding  along  the  same  course, 
has  developed  an  interesting  theory  of  the  evolution  of 
chronic  morbid  states  whose  etiology  and  pathogenicity  are 
today  so  little  understood  and  whose  treatment  is  therefore 
as  difficult  as  it  is  unsatisfactory. 

The  book  should  be  of  interest  to  those  who  recognize 
the  importance  of  a  comprehension  of  the  principles  under- 
lying the  study  and  treatment  of  disease. 

The  translator  wishes  to  thank  Mr.  G.  S.  S.  Playfair  for 
much  valuable  assistance  in  the  translation. 

F.  M.  R. 

35901 


Digitized  by  the  Internet  Archive 

in  2007  with  funding  from 

IVIicrosoft  Corporation 


http://www.archive.org/details/evolutionofdiseaOOdanyrich 


PREFACE. 


As 'the  study  of  physical  and  biological  phenomena,  of 
the  constitution  of  matter  and  of  its  manifestations  becomes 
more  extended  and  more  precise,  it  tends  to  prove  that  the 
perpetual  changes  noticed  in  all  things,  consist  in  an  uninter- 
rupted series  of  decompositions  and  syntheses;  and  as  the 
transformations  of  any  one  substance  have  a  beginning  and 
an  end,  it  can  be  said  that  any  substance  in  process  of  change 
undergoes  an  evolution  of  which  the  different  successive 
phases  are  determined  by  the  physical  and  chemical  proper- 
ties of  its  constituent  elements.' 

Decompositions  follow,  as  a  rule,  a  very  uniform  path  and 
lead  to  simple  elements  which  may  be  considered  as  definite. 
Synthesis,  on  the  other  hand,  is  itself  subject  to  evolution; 
it  leads  step  by  step  to  compounds  that  are  more  and  more 
complicated,  varied  and  numerous,  and  it  is  impossible  to 
predict  any  end  to  these  changes. 

The  final  result  of  natural  synthesis,  the  most  complicated 
and  the  most  perfect  product  known  to  us,  is  the  chemical 
species  which  we  may  call  "albuminoid  micelle."^  Its 
characteristic  is  that  it  rebuilds  itself  as  it  wears  out,  or,  in 
other  words,  that  it  is  continuously  undergoing  partial 
decomposition  and  at  the  same  time  a  reconstruction  of  the 

^  The  word  "micelle"  is  used  to  define  the  units  of  albuminoid  matter  of 
every  colloid  in  the  same  sense  that  the  word  "molecule"  expresses  the 
unit  of  chemical  compounds.  The  word  "particle"  is  used  by  many  Ameri- 
can authors  in  the  same  sense. 


vi  PREFACE 

decomposed  elements  with  simpler  elements  found  in  its 
environment,  so  that  although  always  in  an  unstable  equilib- 
rium, it  constantly  retains  its  initial  composition  and 
structure. 

It  is  easy  to  conceive  that  if  the  conditions  of  this  "  nutri- 
tion" of  the  "micelle"  depend  on  what  is  provided  by  the 
surrounding  matter,  the  "micelle"  may  decrease  or  increase 
in  volume;  that  is  to  say,  it  may  decompose  faster  or  slower 
than  it  is  constructed .  When  a  sufficient  quantity  of  building 
material  is  at  hand,  the  increase  in  volume  will  predominate ; 
and  when  its  volume  will  have  reached  certain  limits  capable 
of  modifying  its  conditions  of  normal  nutrition,  the  "micelle" 
will  split  into  two  equal  parts. 

It  is  this  muUiplicaticm  which  together  with  nutrition 
constitutes  life. 

The  "micelle"  develops  as  an  individual  and  as  a  species; 
in  its  evolution  it  must  obey  the  law  which  obliges  every 
substance  to  replace  in  its  complexes,  the  less  stable  or  more 
soluble  compounds  by  more  stable  or  less  soluble  compounds. 

The  "micelle"  will  "age"  because,  as  its  elements  become 
more  stable,  substitution  becomes  slower  and  slower;  it  will 
"die"  when  stabilization  will  have  passed  beyond  certain 
Hmits,  because  a  certain  rapidity  of  exchange,  producing  a 
certain  amount  of  heat,  in  a  given  time,  is  an  indispensable 
condition  of  life. 

The  individual  may  die  under  these  conditions;  the  species 
likewise,  because  the  child-"  micelles"  will  inherit  the  degree 
of  stability  acquired  by  the  parent-"  micelles." 

When  a  cell's  "micelles"  find  in  their  surrounding  medium 
elements  of  which  they  are  composed  themselves,  or  other 
elements  for  which  their  own  elements  have  no  affinity,  they 
can  find  nourishment  and  can  develop  in  a  normal  manner; 
but  when,  on  the  contrary,  they  find  strange  elements, 


PREFACE  vii 

requiring  fixation  by  their  affinities,  the  nutritive  equilibrium 
will  be  modified;  and  when  the  proportion  of  * 'micelles"  so 
affected  among  the  "micelles"  composing  the  plasma  of  the 
cell,  will  have  passed  beyond  certain  limits,  the  cell  itself  will 
become  diseased  and  may  die. 

These  are  the  general  ideas  which  have  guided  us  in  the 
following  study  of  pathological  states. 

In  Part  II  the  secondary  consequences  in  the  organism  of 
the  conditions  of  immunity  and  anaphylaxis,  which  result 
from  recovery  in  infectious  disease,  or  from  an  habitual  or 
periodical  digestion  of  antigens  are  discussed. 

The  study  of  these  questions  has  led  to  the  conclusion  that 
all  the  chronic  morbid  states  with  their  periods  of  acute  crises 
alternating  with  longer  or  shorter  remissions,  originate  from 
antigens,  and  are  determined  by  the  state  of  immunity- 
anaphylaxis  of  the  organism.  The  necessary  experimental 
confirmation  of  this  hypothesis  has  shown  in  reality  that  the 
anti-anaphylactic  treatment  is  of  unquestionable  efficacy 
in  all  those  chronic  diseases  in  which  we  have  been  able  to 
apply  it  up  to  date  (except  organic  mental  diseases)  and  a 
long  series  of  observations  corroborates  this. 

We  have  obtained  these  results  by  non-specific  antigens 
and  in  order  to  explain  the  curative  action  of  these  antigens, 
we  have  been  obliged  to  assume  the  direct  and  predominating 
intervention  of  the  nervous  centers. 

The  work  is  concluded  by  a  general  theory  of  immunity, 
anaphylaxis,  and  anti-anaphylaxis,  based  on  the  structure, 
properties  and  function  of  the  organism,  and  of  the  structural 
and  functional  units  composing  it. 

J.  Danysz. 


CONTENTS. 


PART  I. 


CHAPTER  I. 


The  Theories  of  Immunity  (Metchnikoff  and  Ehrlich).    Experi- 
mental Researches  Inspired  by  These  Theories. 

Pathogenic  Mechanism  of  Bacterial  Infection.  Toxic 
Action.  Action  of  Bacterial  Bodies  and  of  the  Products 
of  Bacteriolysis  when  Considered  as  Heterogeneous 
Albumins.  Properties  of  the  Mixtures  of  Antigens  with 
Their  Antibodies.  Ricin.  Antiricin.  Phenomena  of 
"Surcharge" 17-32 


CHAPTER  II. 


Physicochemical   Properties.     Transformation  of  the 
Arsenobenzenes  "In  Vitro"  and  in  the  Organism. 

Physicochemical  Properties  and  Constitution.  Transforma- 
tions "In  Vitro."  Transformations  in  the  Organism 
Toxicity.  Relations  between  Apparent  Toxicity  and 
Formation  of  Precipitates.  Reactions  of  the  Organism. 
Formation  of  a  Specific  Antibody.  Experiments  on  the 
Fixation  and  Elimination  of  Luargol  by  the  Organism  .         33-44 


X  CONTENTS 

CHAPTER  III. 

Evolution  of  the  Infectious  Diseases. 

(1)  Diphtheria.     Action  of  Toxin  on  the  Tissues.     Fixation 

"en  Surcharge"  of  Toxin.  Experiments.  Properties 
of  Mixtures  of  Toxin  with  Antitoxin.  Immunity. 
Cure  by  Antitoxin. 

(2)  TuhercuLosis.  Action  of  Tuberculin.  Action  of  Bacter- 
ial Bodies.  Antituberculin  and  Antibacillin.  The  Sur- 
charge of  the  Organism  by  Antibodies  Causes  Patho- 
logical Manifestations.     Auto-reinfections. 

(3)  Typhoid  and  Paratyphoid  Fevers.  Cholera.  Mechanism 
of  Gastro-intestinal  Infections.  Formation  and  Action 
of  Precipitating  Antibodies.  Exotoxins  and  Endotoxins. 
Nature  of  the  Pathological  Symptoms  in  the  Period  of 
Disease.  Mechanism  of  Spontaneous  Cure.  Patho- 
genicity of  Ahmentary  Poisoning  by  Paratyphoid. 
Pathogenicity  and  Nature  of  Cholera  Crisis       .      .      .         45-73 

CHAPTER  IV. 

Mechanism  of  Infection.     Infection  or  Contagion.     Virulence. 
Immunity.    Refractory  State. 

Means  of  Adaptation  of  Bacteria  to  the  Interior  of  the 
Organism.  Origin  of  the  Affinities  between  the  Anti- 
gens and  the  Normal  Antibodies.  Immunity  and 
Reciprocal  Anaphylaxis  of  Infecting  Bacteria  and  of 
Infected  Organisms.  Experiments  on  the  Pathogenesis 
of  Paratyphoids  and  of  Rat  Anthrax 74-81 

CHAPTER  V. 

Immunity  and  Anaphylaxis. 

Formation  of  Immunizing  and  Anaphylactic  Antibodies. 
Reason  for  the  Existence  of  Anaphylaxis.  Nature  of 
the  Antigens.  Colloids.  Constitution  and  Physico- 
chemical  Properties  of  Particles.  Combinations  of 
Colloids  with  Salts  in  Varying  Proportions.  Action 
.   and  Nature  of  Antibodies 82-108 


CONTENTS  xi 


CHAPTER  VI. 

Influence  of  the  Central  Nervous  System  on  Immunizing 
Reactions  and  on  Anaphylaxis. 

Pathological  Manifestations  Caused  by  Emotion.  Action  of 
Hypnotic  and  Anesthetic  Agents  on  Anaphylactic  Shock. 
Experiments  by  Roux  and  Besredka.  Action  of  Violent 
Emotions  on  the  Metabolism  of  the  Suprarenal  Capsules. 
Kendall's  experiments 109-113 


CHAPTER  VII. 

Therapeutic  Measures. 

Latent  Anaphylaxis.  Actual  Anaphylaxis.  Specificity  of 
Antigens  in  their  Vaccinating  and  Curative  Action. 
Preventive  and  Curative  Action  of  Non-specific  Anti- 
gens. Skepto-  or  Tachyphylaxis.  Anti-anaphylatox- 
ins.  Uniformity  of  Reactions  in  Anaphylactic  and 
Anaphylatoxic  Crises.  Chemotherapy.  Bacteriother- 
apy.     Serum  Therapy 114-123 


CHAPTER  VIII. 

Principles  of  the  Classification  of  Infectious  Diseases. 

Constitution  and  Physicochemical  Properties  of  Albuminoid 

Particles.  Normal  and  Abnormal  Nutrition    ....     124-127 

CHAPTER  IX. 

General  Conclusions. 

The  Organism.     Its  Physicochemical  Composition.     Prop- 
erties of  the  "Micelle" 128-134 


xii  CONTENTS 


PART  11. 


CHAPTER  X. 
Evolution  of  Theories  Concerning  Immunity,  Anaphylaxis 

AND  AnTI-ANAPHYLAXIS. 

Introduction.  Researches  by  Pasteur,  Roux  and  Yersin, 
Behring  and  Kitasato.  Transfusion  of  Blood  and  Injec- 
tion of  Heterologous  and  Homologous  Sera  and  Other 
Proteins.  Anaphylaxis.  Anti-anaphylaxis  and  the 
Immunization  of  Animals.  Mechanism  of  Anti-ana- 
phylaxis. Tachyphylaxis  or  Skeptophylaxis.  Physio- 
logical and  Physicochemical  Causes  of  the  Formation 
of  Antibodies  in  Excess  by  Antigenic  Action.  Immed- 
iate and  Secondary  Results  of  the  Condition  of  Immun- 
ity-anaphylaxis.  Origin  of  Chronic  Non-contagious 
Diseases 135-161 


CHAPTER  XL 

Principles  of  the  Anti-anaphylactic  Treatment  of  Chronic 
Diseases  by  Entero-antigens. 

Case  Reports.  A.  Dermatoses  (Cases  1  and  2,  4  to  7  inclu- 
sive, and  9).  B.  Asthma  (Cases  10  to  12  inclusive). 
C.  Other  Cases.  Summary  of  Observations.  General 
and  Local  Reactions  Caused  in  the  Organism  by  Entero- 
antigens.  Theory  of  Curative  Reactions.  Kendall's 
Experiment.     The  Influence  of  the  Nervous  System     .       162-184 


CHAPTER  XII. 

General  Summary:  Theoretical  Deductions. 

Theory  of  Immunity,  of  Anaphylaxis  and  of  Anti-anaphy- 
laxis           185-194 


EVOLUTION  OF  DISEASE, 


PART  L 


CHAPTER  I. 

THEORIES  OF  IMMUNITY  OF  METCHNIKOFF 
AND  EHRLICH. 


Experimental  Researches  Inspired  by  These  Theories  y/      It     Si  l\   (r 

Medical  science  has  for  its  object  to  teach  us  why  and  ^j/ 
how  an  organism  becomes  diseased,  what  constitutes  this  Wf 
disease,  and  how  cure  is  effected.  It  is  only  by  knowing  how 
to  answer  these  three  questions  that  it  is  possible  to  treat 
disease  successfully  either  by  preventing  its  occurrence  or 
by  assisting  the  organism  in  recovering  from  it.  Up  to  the 
time  of  Pasteur  we  knew  as  pathogenic  agents  only  poisons 
as  such;  chemically  crystallizable  products  and  venins,  all 
of  unknown  composition,  but  which  with  the  crystalloids 
have  this  fact  in  common,  that  the  diseases  of  which  they 
are  the  cause  are  non-contagious. 

With  the  discovery  of  bacteria  we  began  to  know  the  origin 
of  contagious  diseases  and  it  was  recognized  at  about  the 
same  time,  that  if  a  certain  microbe  was  the  primary  cause 
of  the  disease  it  could  act  only  by  means  of  its  soluble  secre- 
tions or  by  products  which  were  allowed  to  escape  at  its 
death;  that  is  to  say,  by  poisons  of  an  unknown  composition 
analogous  to  the  venins.  But  although  we  know  the  cause  of 
disease,  we  do  not  know  the  mechanism  by  which  the  patho- 


18  THEORIES  OF  IMMUNITY 

logic  state  is  brought  about.  The  symptoms  and  the  ana- 
tomical lesions  of  disease  were  recognized  but  it  was  not  known 
how  these  symptoms  and  lesions  were  produced.  It  was 
learned  how  to  "accustom"  the  organism  to  certain  poisons, 
to  "vaccinate"  against  certain  diseases  and  to  effect  cure  by 
certain  antidotes.  But  we  have  been  obliged  to  recognize 
that  methods,  either  preventive  or  curative,  applied  with 
success  in  certain  cases,  do  not  give  any  appreciable  result 
in  others. 

Thus  neither  the  mechanism  of  the  pathogenicity  nor  that 
of  the  pathologic  state  nor  that  of  the  cure  was  understood, 
so  that  curative  measures  were  necessarily  limited  to  attempts 
to  relieve  symptoms  and  to  the  treatment  of  lesions  by  means 
found  by  chance  experiments. 

In  order  to  throw  light  on  the  mechanism  of  cure,  especially 
in  the  infectious  diseases,  Metchnikoff  put  forth  his  phago- 
cytic theory,  according  to  which,  the  leukocytes,  the  only 
cells  of  the  organism  provided  with  a  membrane  which  could 
engulf  microbes,  digested  these  microbes  and  thus  destroyed 
the  primary  cause  of  the  disease. 

However,  much  before  the  phagocytic  theory,  vaccina- 
tion of  the  organism  against  smallpox,  anthrax,  erysipelas, 
chicken  cholera,  carbuncle,  had  been  successful.  The  first 
practical  results  in  the  curative  treatment  of  an  infectious 
disease,  viz.,  the  cure  of  diphtheria  by  antitoxic  serum,  did 
not  result  from  the  conception  of  immunization  by  leukocytes. 

Vaccination  by  soluble  bacterial  secretions  had  been 
observed  in  numerous  diseases,  as  for  example:  by  Chauveau 
in  lambs  born  of  ewes  inoculated  with  anthrax  during  ges- 
tation; by  Salmon  and  Smith  in  their  experiments  in  hog 
cholera;  by  Charrin  in  pyocyaneous  infection  and  by  Roux 
and  Chamberland  in  symptomatic  anthrax  and  the  infection 
by  septic  vibrio.  Moreover  the  production  of  an  antitoxin 
"in  excess"  for  diphtheria  and  tetanus  following  injection 
of  toxins  filtered  from  both  living  and  dead  organisms  was 
demonstrated;  as  well  as  the  fact  that  these  bacterial  poisons 
might  be  fixed  to  and  might  act  not  only  on  the  leukocytes 
but  also  on  every  other  cell. 

These  observations  inspired  Ehrlich  to  a  more  general 


THEORIES  OF  IMMUNITY  19 

conception  not  only  of  the  mechanism  of  cure  but  also  that 
of  the  pathogenicity.  Without  denying  the  possibility  of 
the  intervention  of  leukocytes  Ehrlich  propounded  the  idea 
of  indispensable  chemical  affinities  for  every  reaction  between 
two  substances:  taking  the  same  point  of  view  for  every 
reaction,  whether  immunizing  or  pathogenic,  between  bac- 
terial poisons  and  the  cells :  namely,  that  some  one  substance 
of  the  cell  possesses  a  chemical  affinity  for  these  poisons. 
Pathologic  symptoms  are  then  the  result  of  fixation  of  poisons 
by  cellular  substance  and  cure  is  the  result  of  the  multiplica- 
tion of  this  cellular  substance  neutralized  by  poison,  which 
the  cell  produces  in  excess.  The  product  of  the  combination 
ought  necessarily  to  be  neutral.  . 

We  shall  see  further  what  there  is  to  take  or  leave  in  this 
theory  which  Ehrlich  formulated.  It  will  suffiiqe  to  note, 
at  the  moment,  that  Ehrlich's  theory  was  no  more  capable 
than  that  of  Metchnikoff  of  explaining  the  evolution  of  every 
disease,  and  that  it  could  not  explain  the  reaction  provoked 
in  the  organism  by  bacterial  poisons,  or  the  necessity  or 
possibility  of  the  organism  reacting  to  certain  poisons  in  a 
way  different  from  that  in  which  it  reacts  to  many  other 
poisons. 

But  even  if  the  purely  biologic  theory  of  Metchnikoff  as 
well  as  the  purely  biochemical  theory  of  Ehrlich  cannot 
explain  the  entire  mechanism  of  pathogenicity  and  immunity, 
yet  each  contains  certain  truths  which  have  been  the  basis 
of  countless  studies  in  the  domains  of  biology,  biochemistry 
and  biophysics.  These  studies  have  made  possible  the  dis- 
covery and  the  definition  of  a  great  number  of  facts  concern- 
ing the  properties  of  pathogenic  agents,  the  nature  and  the 
mechanism  of  their  action  on  the  organism,  the  reactions 
which  they  provoke,  the  nature  and  properties  of  the  products 
of  their  reactions  with  the  fluids  of  the  organism  both  in 
vitro  and  in  vim. 

Notably  so,  these  studies  have  allowed  us  to  establish  a 
very  fine  distinction  between  these  pathogenic  agents,  which 
are  cry stalliz able  and  those  which  are  not:  these  latter  being 
grouped  under  the  general  name  of  colloids.  These  studies 
have  permitted  us  to  enlarge  the  horizon,  to  clarify  and  to 


20  THEORIES  OF  IMMUNITY 

better  understand  the  true  significance  of  facts  in  daily 
experience  and  to  better  group  these  facts  in  order  to  con- 
struct a  general  idea  which  in  its  turn  will  point  the  way 
toward  new  researches.  In  the  discussion  which  follows  we 
shall  try  to  recall  the  merits  of  the  two  theories  of  Metchnikoff 
and  Ehrlich  and  of  the  experimental  researches  which  these 
have  inspired.  We  shall  try  to  interpret  the  results  of  these 
researches  in  the  light  of  new  facts  and  to  draw  from  the  total 
of  these  studies  conclusions  which  are  necessarily  logical. 

Metchnikoff 's  theory  of  immunity  attributed  the  defensive 
mechanism  of  the  organism  against  pathogenic  germs  exclu- 
sively to  the  leukocytes.  Leukocytes  engulf  the  germs, 
digest  them  and  there  results  an  overproduction  of  a  specific 
digestive  ferment  which  renders  this  digestion  more  and  more 
easy  and  active.  When  all  the  microbes  are  thus  destroyed, 
there  is  cure  and  the  organism  remains  immunized  against 
the  same  germ  because  the  leukocytes  which  have  learned 
to  digest  these  germs  retain  this  new  property  for  a  certain 
time  and  transmit  it  by  heredity  to  their  descendants  so  that 
they  also  will  be  able  to  attack  a  small  quantity  of  the  same 
parasites  in  case  the  organism  again  becomes  spontaneously 
infected. 

We  may  easily  understand  the  destruction  of  the  microbes 
in  the  interior  of  the  leukocytes.  The  role  of  these  latter  in 
the  defense  of  the  organism  is  certainly  very  important  but 
we  must  recall  that  if  the  phagocytic  theory  contains  one 
part  of  the  truth  it  cannot  include  the  whole  problem  of 
pathogenicity  and  immunity  because  the  struggle  between 
microbes  and  organism  does  not  take  place  exclusively  in 
the  blood.  If  we  must  assume  that  it  is  the  microbe  which 
is  the  origin  of  disease  and  that  its  destruction  by  the  white 
blood  corpuscles  can  lead  to  cure,  it  is  by  no  means  less 
certain  that  it  is  not  only  the  microbe  body  but  also  and  often 
principally  the  soluble  products  or  poisons  which  it  secretes 
during  its  life  or  which  are  allowed  to  difflise  after  its  death 
that  by  acting  not  only  on  the  leukocytes  but  also  on  a  large 
number  of  other  cells,  produce  the  lesions  and  symptoms 
characteristic  of  each  disease. 

Pathologic  manifestations  can  be  only  the  results  of  reac- 


THEORIES  OF  IMMUNITY  21 

tions  between  cells  and  bacterial  poisons.  When  the  cells 
do  not  succumb  in  the  struggle  they  become  more  resistant 
to  the  action  of  the  same  poison.  But  the  presence  and  the 
destruction  of  bacteria  in  the  organism  may  provoke  reactions 
of  still  another  nature.  The  poisons  which  they  excrete  are 
not  the  only  substances  of  which  the  protoplasm  and  the 
membrane  of  the  bacterial  body  are  composed.  There  are 
albumins  which  without  being  poisonous  are  not  harmless 
for  the  organism.  These  albuminous  substances  themselves 
must  be  transformed  in  order  to  be  assimilated  and  there 
may  result  from  them  disturbances  which  we  will  discuss 
later  when  we  come  to  treat  of  pathologic  states  provoked 
by  the  injection  of  albumin.  It  is  sufficient  to  note  here 
provisionally  that  we  have  to  consider  an  intravascular 
immunity  which  may  be  explained  in  many  cases  by  the 
phagocytic  theory  of  Metchnikoff  as  well  as  a  cellular  immun- 
ity which  is  not  so  explained  and  which  is  the  object  of  the 
biochemical  theory  formulated  by  Ehrlich. 

Ehrlich's  theory  has  for  its  basis,  as  we  have  seen,  the 
general  conception  that  a  reaction  between  two  substances 
is  possible  and  can  be  determined  only  by  chemical  affinities 
between  these  substances:  and  it  would  seem  evident  that  a 
body  which  is  insoluble  in  the  fluids  of  the  organism  can 
exercise  only  a  purely  mechanical  action  on  the  fluids  and 
the  tissues.  Not  being  able  to  form  any  combination,  it 
cannot  produce  a  reaction  or  any  disturbance  in  the  existing 
equilibrium. 

Ehrlich  pictures  the  process  of  immunization  in  the  follow- 
ing manner:  a  toxin  is  attracted  and  fixed  by  a  cellular  sub- 
stance which  possesses  a  chemical  affinity  for  it:  the  toxin 
neutralizes  this  substance  and  is  itself  neutralized.  The 
neutral  product  thus  formed  is  expelled  from  the  cell  as  use- 
less and  as  the  cell  cannot  be  permanently  deprived  of  the 
substance  which  the  toxin  has  neutralized  and  which  we  will 
call  normal  antibody,  it  reproduces  not  only  as  much  as  is  lost, 
but  a  little  more;  it  is  the  custom  of  every  living  cell  to  react 
to  any  sort  of  excitation  by  a  multiplication  of  the  substance 
excited,  or,  in  other  words,  by  a  reinforcement  of  the  tis- 
sues and  of  the  organs  excited  in  order  to  be  able  to  support 


22  THEORIES  OF  IMMUNITY 

future  excitations  with  less  danger  and  fatigue.  But  it  often 
happens  that  the  cell  in  this  process  of  defense  and  rehabili- 
tation exceeds  the  normal  reaction:  it  makes  a  "normal 
antibody"  in  much  larger  quantity  than  it  can  use  and  then 
expels  the  excess,  which  passes  into  the  blood  and  the  fluids 
to  become  antibody  in  excess  or  antitoxin,  which,  is  found  in  the 
serum  of  a  hyperimmunized  animal  and  which  may  be  used 
to  cure  disease  in  another  subject,  provided  this  disease  is 
caused  by  the  same  toxin  secreted  by  the  same  germ. 

Antibody-in-excess  is  then  a  substance  which,  according 
to  its  definition,  does  not  need  to  be  transformed  in  order  to 
be  assimilated.  It  is  "homologous"  for  the  organism  and 
may  be  considered  as  a  sort  of  "substance  in  reserve"  which 
the  organism  may  resorb  according  to  its  need. 

Such  as  it  was  formulated  by  Ehrlich  the  theory  of  immun- 
ity based  on  the  general  principles  of  chemical  affinities  is 
applicable  in  reality  to  only  a  small  number  of  special  dis- 
eases caused  exclusively  by  certain  toxins  as  diphtheria  and 
tetanus  and  even  in  these  cases  Ehrlich  was  obliged  to  add 
purely  hypothetical  distinctions  between  certain  properties 
"toxophores"  and  "  haptophores"  of  each  toxin  to  explain 
and  distinguish  their  pathogenic  and  their  immunizing 
action. 

As  to  the  mechanism  by  which  a  pathologic  state  could 
be  provoked  in  an  organism  by  infection;  as  to  the  question 
of  knowing  why  different  diseases  differed  from  each  other 
by  a  special  evolution  and  by  a  total  of  symptoms  more  or 
less  characteristic  to  each;  why  in  certain  cases  the  processes 
of  immunization  are  complicated  by  an  inverse  process  known 
since  the  time  of  Charles  Richet  as  "anaphylaxis";  and 
finally,  why  there  are  certain  substances  for  which  the  organ- 
ism makes  specific  "antibodies"  and  others  for  which  it  does 
not  make  them,  as  well  as  other  questions,  neither  the  one 
nor  the  other  of  the  two  theories  can  explain. 

Should  we  conclude  that  these  theories  cannot  be  of  any 
use  because  they  are  almost  always  incomplete  and  inade- 
quate?   Certainly  not! 

General  ideas  are  always  necessary  to  stimulate  the  studies 
of  new  generations  along  new  lines. 


THEORIES  OF  IMMUNITY  23 

All  the  works  on  serum  diagnosis  by  Bordet  and  Gengou, 
Besredka,  Widal,  Wassermann,  and  others,  are  the  direct 
emanation  from  the  ideas  of  Metchnikoff.  Modern  chemo- 
therapy is  a  creation  of  Ehrlich  and  his  pupils.  And  all  these 
studies  which  have  confirmed  in  part  the  theories  of  these 
two  great  savants  have  had  at  the  same  time  the  result  of 
exposing  their  faults  and  discrepancies  which  it  has  been 
necessary  to  correct  with  new  researches,  which  in  their  turn 
have  permitted  us  to  formulate  a  theory  more  complete  for 
the  actual  state  of  our  knowledge. 

Today  we  may  conceive  of  a  process  of  immunity  in  the 
most  general  manner  as  a  necessary  reaction  of  the  whole 
organism  against  each  and  every  substance  which  is  not  a 
part  of  the  organism  and  which  is  introduced  into  its  interior 
in  any  way  whatsoever.  From  our  present  point  of  view  we 
may  divide  all  these  substances  into  two  great  groups: 

First,  those  which  on  injection  into  the  organism  provoke 
the  formation  of  "specific  antibodies,"  that  is  to  say,  of  sub- 
stances which  appear  in  the  fluids  and  tissues  of  the  organism, 
some  time  after  the  introduction  of  the  foreign  substance  and 
form  with  these  substances  products  which  are  neutral  or 
active  toward  the  organism. 

Second,  those  to  which  the  organism  may  accustom  itself 
in  a  certain  measure  but  to  which  "specific  antibodies"  are 
not  formed.  To  this  last  group  belong  all  those  substances 
of  a  relatively  simple  and  well  defined  chemical  composition 
such  as  alkaloids,  glucosides,  mineral  salts,  in  a  word,  crys- 
talloids, which  from  the  biophysical  point  of  view,  have  the 
common  property  of  traversing  dialyzing  membranes  and 
of  being  able  to  be  directly  assimilated  or  eliminated.  All 
these  substances  if  they  are  poisonous  belong  to  the  domain 
of  toxicology  and  will  not  be  discussed  here. 

The  substances  of  the  first  group  including  albumins  of 
every  sort,  bacterial  secretions,  venins,  etc.,  have  a  composi- 
tion and  physicochemical  constitution  which  is  much  more 
complicated  and  even  today  imperfectly  understood.  From 
the  biochemical  point  of  view,  they  have  the  common  prop- 
erty of  not  being  able  to  traverse  dialyzing  membranes  and 
under  the  ultramicroscope  they  appear  as  very  fine  granules. 


24  THEORIES  OF  IMMUNITY 

To  these  substances  of  biologic  origin  have  been  added, 
quite  recently,  several  organic  compounds  obtained  synthet- 
ically and  notably  substances  of  the  series  of  arsenobenzenes, 
either  simple  or  multimetallic,  of  which  the  chemical  com- 
position is  well  defined  but  of  which  the  constitution  is  still 
imperfectly  understood. 

The  ability  or  lack  of  ability  to  traverse  dialyzing  mem- 
branes is  the  most  important  distinctive  characteristic  of 
these  two  categories  of  substances  in  their  reaction  on  the 
organism.  Those  which  can  traverse  membranes  rapidly 
penefrate  into  the  tissues,  combining  with  substances  of  the 
organism  according  to  the  laws  of  their  chemical  affinities 
and  produce  immediately  or  at  least  very  rapidly,  effects 
which  are  nutritive,  exciting,  toxic,  hypnotic,  or  anesthetic 
according  to  the  nature  of  the  products  which  they  form 
with  the  cell  contents  and  according  to  the  role  of  the  cells 
in  the  life  of  the  organism.  That  part  which  is  not  fixed  by 
the  tissues  is  quite  rapidly  eliminated  by  the  kidne}^  or  the 
intestines. 

On  the  other  "hand  the  colloids,  which  do  not  traverse  the 
cell  membranes  which  enclose  each  cell,  cannot  be  either 
assimilated  or  fixed  by  the  tissues  or  eliminated  without 
being  subjected  to  a  special  transformation.  The  charac- 
teristic feature  which  results  is  the  relative  delay  of  the 
reactions  which  they  provoke  in  the  organism.  Furthermore, 
we  must  well  understand  that  there  are  no  absolutely  sharp 
distinctions  between  colloids  and  crystalloids. 

In  setting  up  a  series  of  more  or  less  permeable  dialyzing 
membranes  it  is  recognized  that  certain  colloids  traverse 
certain  membranes  which  others  do  not  traverse,  and  that 
the  same  membranes  may  allow  one  part  of  one  colloid  to 
pass  without  the  other.  Thus  a  given  membrane  may  pass 
diphtheria  toxin  more  easily  than  antitoxin  and  the  toxin 
will  be  only  partially  eliminated  or  dialj^zed.  We  must 
necessarily  conclude  that  all  colloids,  from  the  point  of  view 
of  the  size  of  the  granules  of  which  they  are  composed  are 
not  identical,  that  a  colloid  is  not  absolutely  homogeneous 
in  all  its  parts,  that  it  is  composed  of  granules  larger  or  smaller, 
that  is  to  say,  of  granules  containing  a  larger  or  smaller 
number  of  molecules. 


THEORIES  OF  IMMUNITY  25 

When  a  certain  quantity  of  such  a  product  is  injected  into 
the  blood  of  an  animal  it  is  found  at  the  end  of  twenty-four 
hours  that  one  part  has  been  able  to  penetrate  into  the  tis- 
sues and  has  been  fixed  in  the  cells,  a  second  part  has  been 
eliminated,  while  a  third  part  is  still  found  to  circulate  in 
the  blood.  Thus  in  the  case  of  disodoluargol  (the  disodium 
salt  of  dioxydiaminoarsenobenzene-antimonious-silver-bro- 
mide) ;  if  10  eg.  are  injected  into  a  rabbit's  vein,  after  twenty- 
four  hours  there  will  be  found  of  it  about  a  quarter  in  the 
excretions  and  a  quarter  in  the  blood  and  we  ought  to  con- 
clude that  the  other  two  quarters  have  been  absorbed  and 
fixed  by  the  organs  and  tissues.  Three-quarters  of  the 
injected  product  have  thus  been  able  to  traverse  cellular 
membranes  within  twenty-four  hours  while  the  final  quarter 
composed  of  larger  granules  has  not  been  transformed  into  a 
dialyzable  product. 

For  each  colloid  the  proportions  may  be  different  but  for 
the  colloids  of  biologic  origin  we  are  unable  to  evaluate  them 
accurately  because  we  do  not  know  the  chemical  constitution. 
We  cannot  conceive  an  idea  of  their  quantity  by  biologic 
reactions  which  are  always  uncertain.  But  w^e  do  know  with 
certainty  that,  as  in  the  case  of  the  arsenobenzenes,  albumins, 
like  the  toxins  injected  into  the  blood,  are  partly  fixed  by  the 
tissues  some  hours  or  some  days  after  the  injection;  because 
we  see  these  tissues  react  with  characteristic  symptoms  and 
we  know  that  no  part  of  these  products  circulates  for  a  long 
time  in  the  blood  without  being  modified.  Toxins  generally 
remain  longer  in  circulation  than  albumins  (white  of  egg, 
serum,  etc.).  Thus  we  may  conclude  that  they  are  more 
fluid  and  less  colloidal,  than  these  latter. 

We  have  seen  above  that  all  colloidal  substances  on  which 
experiments  have  been  made  up  to  the  present  time  have, 
from  a  biological  point  of  view,  another  character  in  common: 
injected  into  the  blood  or  under  the  skin  of  an  animal,  they 
cause,  after  a  variable  incubation  period,  the  formation  of 
"antibodies  in  excess,"  that  is  to  say,  of  products  which 
exert  certain  specific  actions  on  themselves. 

For  want  of  a  better  term  all  these  substances  have  been 
grouped  as  "antigens"  precisely  because  they  provoke  the 


26  THEORIES  OF  IMMUNITY 

formation  of  "antibodies"  and  at  the  moment  they  can 
hardly  be  called  anything  else  because  all  we  know  of  them 
except  in  the  case  of  arsenobenzene,  is  that  they  are  recipro- 
cally *'anti."  When  after  a  preparatory  treatment,  the  in- 
tensity and  duration  of  which  may  vary  widely  for  different 
antigens  and  different  animals,  the  prepared  animal  is  bled 
and  the  blood  serum  mixed  with  the  antigen  in  a  test-tube, 
reactions  are  seen  which  are  not  produced  with  the  serum  of  a 
normal  animal  and  which  are  different  according  to  the  nature 
of  the  antigen  injected. 

Toxins  (diphtheria,  tetanus,  botulism),  soiiie  venins  and 
poisons  of  certain  mushrooms  cause  the  formation  of  anti- 
bodies which  neutralize  the  pathogenic  effects  of  these  poisons 
without  visible  change.  The  mixture  of  the  two  liquids 
remains  clear  and  one  can  determine  neutralization  of  the 
"antigen"  only  by  injecting  the  mixture  into  a  susceptible 
animal.  After  a  sufficient  preparation,  a  relatively  very 
small  quantity  of  the  blood  serum  of  the  treated  animal  is 
able  to  neutralize  a  large  number  of  "lethal  doses"  of  the 
antigen.  One  cubic  centimeter  of  antitetanic  serum  may, 
for  example,  often  neutralize  a  thousand  or  even  more  times 
the  dose  of  toxin  necessary  to  kill  a  guinea-pig  and  it  is  this 
property  of  the  antibody  discovered  by  Behring  and  Kitasato 
which  E.  Roux  first  utilized  in  the  practical  serum  treatment 
of  diphtheria  arid  in  the  preventive  treatment  of  tetanus 
and  which  Calmette  also  used  in  the  preparation  of  anti- 
venomous  serum. 

Ricin,  a  vegetable  antigen  extracted  from  rice,  whose  com- 
position is  unknown  but  whose  effects  on  the  organism  pre- 
sented many  analogies  with  that  of  diphtheria  toxin,  forms 
with  its  antibody  an  insoluble  compound.  When  antiricin 
serum  is  added  to  a  solution  of  ricin  a  precipitate  is  formed 
and  if  the  two  solutions  have  been  mixed  in  suitable  propor- 
tions the  supernatant  fluid  will  contain  neither  ricin  nor  free 
antiricin.  We  have  been  able  to  conclude  then  that  a  part 
if  not  all  the  antigen  and  antibody  are  combined  or  fixed  one 
by  the  other  and  are  contained  in  the  precipitate  and  this 
supposition  has  been  confirmed  by  experiment.  By  sub- 
mitting the  precipitate  to  the  action  of  gastric  juice  which 


THEORIES  OF  IMMUNITY  27 

destroys  the  antibody  and  does  not  destroy  the  riein,  it  is 
possible  to  recover  the  ricin  which  the  precipitate  contains. 

Ricin  presents  another  peculiarity  which  permits  us  to 
study  with  a  little  more  precision  what  it  has  not  been  possible 
to  study  with  diphtheria  and  with  tetanus  toxin.  Ricin 
dissolves  red  blood  corpuscles  in  the  test-tube.  This  pecu- 
liarity is  very  precious  because  it  permits  us  to  make  a  large 
number  of  tests  under  identical  conditions  and  which  are  in 
consequence  exactly  comparable;  for  example,  to  estimate 
the  pathogenic  dose  of  diphtheria  toxin  or,  in  other  words, 
to  establish  a  "unit  of  measure,"  it  is  necessary  to  inject 
different  quantities  into  a  very  large  number  of  animals. 
Each  animal  can  be  injected  only  once  and  as  there  are  very 
appreciable  individual  differences  between  the  animals  from 
the  point  of  view  of  their  sensitiveness  to  the  action  of  toxin, 
even  when  they  are  of  the  same  age,  of  the  same  weight  and 
apparently  of  the  same  species,  one  can  obtain  units  of  meas- 
ure of  only  an  approximate  value,  sufficiently  exact  for  the 
practical  use  of  antitoxic  serum  but  insufficient  for  the  study 
of  the  mechanism  of  the  reactions. 

With  ricin  the  same  solution  (relatively  more  stable  than 
that  of  bacterial  toxins)  can  be  made  to  act  in  the  test-tube  on 
the  same  blood  cells  of  the  same  animal  and  these  tests  can 
be  multiplied  almost  indefinitely  so  that  ''units  of  measure" 
can  be  much  more  exactly  obtained. 

By  studying  the  reaction  of  ricin  and  antiricin  in  the  pres- 
ence of  blood  cells  it  has  been  made  possible  to  discover  what 
one  may  call  the  phenomenon  of  surcharge,  that  is  to  say,  the 
property  of  antigens  to  combine  with  their  antibodies  in 
variable  proportions  and  not  according  to  the  immutable 
law  of  equivalents  established  for  chemical  combinations 
as  such.  Thus,  for  example,  when  we  mix  one  hundred  toxic 
units  of  ricin  with  one  hundred  antitoxic  units,  presumably 
well  titrated,  a  neutral  mixture  is  obtained;  but  when  the 
hundred  toxic  units  are  added  in  fractions  of  five  or  of  ten 
units  to  one  hundred  units  of  antitoxin,  a  mixture  is  obtained 
in  which  there  will  be  a  certain  number  (five  to  fifty  accord- 
ing to  circumstances)  of  free  toxic  units.  This  fact  has  been 
verified  for  other  toxins  and  antitoxins  and  the  conclusion 


28  THEORIES  OF  IMMUNITY 

follows  that  in  mixtures  of  toxins  with  their  antitoxins  or  in 
general,  of  antigens  with  their  antibodies,  there  are  not 
produced  chemical  combinations  in  the  ordinary  sense  but 
certain  states  of  equilibrium  which  are  variable  for  each 
concentration  or  proportion  of  one  product  in  the  other; 
in  other  words,  if  in  certain  proportions,  two  products  can 
exactly  neutralize  each  other,  either  of  them  can  fix  its  "anti" 
en  surcharge. 

We  will  see  further  how  this  theory  which  results  from 
facts  established  by  very  exact  experiments  is  important  in 
explaining  the  biologic  action  of  antigens.  For  the  moment, 
it  is  necessary  to  remember  that  antigens  may  form  with 
their  antibodies  compounds  which  are  soluble  (in  the  cases  of 
diphtheria  toxin,  tetanus  toxin,  or  venins)  or  compounds 
wTiich  are  insoluble  (in  the  cases  of  ricin  or  abrin).  We  may 
also  say  in  this  last  case  that  the  antibody  precipitates  its 
antigen  and  all  precipitating  antibodies  are  called  "pre- 
cipitins." 

The  discovery  of  antidiphtheritic  serum  gave  birth  to  the 
hope  that  it  would  be  possible  to  prepare  antibodies  specific 
for  every  infectious  disease  of  which  the  bacteria  were  known. 
Thus  after  the  discovery  of  anthrax  vaccine,  it  was  hoped 
that  man  and  the  domestic  animals  could  be  vaccinated 
against  all  the  contagions.  It  has  been  established  that  not 
only  all  the  microbes  and  their  secretions  are  "antigens'' 
but  that  many  other  substances  have  a  similar  property  of 
causing  the  formation  of  specific  antibodies.  But  we  have 
been  obliged  to  remember  that  processes  so  simple  and  so 
efficacious  as  vaccination  against  anthrax  and  serum  therapy 
in  diphtheria  cannot  be  applied  to  every  infection. 

The  action  of  antigens  on  the  organism  including  the 
reactions  which  they  provoke  as  well  as  the  properties  of 
antibodies  and  the  compounds  which  they  form  with  their 
antigens  differ  widely  among  themselves  and  produce  many 
contrary  effects.  Thus  it  is  known  that  the  injection  of 
bacteria,  killed  or  living,  as  well  as  bacterial  secretions  pro- 
vokes in  the  injected  animal  the  formation  of  antibodies 
which  agglutinate  and  precipitate  these  bacteria  "in  vitro''; 
that  in  certain  cases  (cholera)  microbes  are  destroyed  by 


THEORIES  OF  IMMUNITY  29 

their  antibodies  while  in  others  (typhoid)  they  continue  to 
live  and  multiply  without  losing  any  of  their  virulence.  With 
rare  exceptions,  antibacterial  sera  not  only  do  not  cure  dis- 
eases but  are  rather  more  harmful  than  curative  (typhoid, 
plague  cholera,  tuberculosis).  Thus  preventive  vaccination, 
however  efficacious  and  durable  in  small-pox  and  anthrax,  is 
usually  very  precarious  and  transient  in  many  other  diseases. 

A  series  of  facts  have  been  discovered  which  without 
touching  infectious  diseases  directly  have,  from  the  theoretical 
and  practical  point  of  view,  given  interesting  results.  Thus 
it  has  been  recognized  (Bordet)  that  the  serum  or  the  blood 
of  an  animal  of  another  species  provokes  on  injection  the 
formation  of  an  antibody  which  can  precipitate  the  serum 
or  dissolve  the  blood  cells  and  can  precipitate  the  serum  of 
the  first  animal  and  these  researches,  as  well  as  the  discovery 
of  bacterial  precipitins,  have  led  to  the  serum  diagnosis  of  a 
large  number  of  infectious  diseases,  as  well  as  to  the  reaction 
called  "complement  fixation"  (Bordet  and  Gengou,  Wasser- 
mann  and  others). 

In  order  to  understand  the  biologic  action  of  antigens  in 
general,  it  is  necessary  to  consider  at  first  the  characters  of 
the  reactions  which  are  common  to  each  of  them  and  then 
for  each  antigen  to  study: 

1.  Its  direct  and  immediate  action  on  the  blood  and  the 
tissues;  in  other  words,  on  the  normal  antibodies  in  the  blood 
and  cells. 

2.  Its  delayed  action,  that  is  to  say,  its  action  on  the 
''antibodies  in  excess"  which,  after  a  variable  incubation 
period,  will  have  appeared  in  the  organism. 

3.  The  nature  of  its  compounds  with  these  ''antibodies  in 
excess"  as  well  as  the  reactions  which  these  compounds  may 
call  forth  in  the  tissues  and  in  the  blood. 

It  is  very  difficult  to  appreciate  accurately  the  direct  and 
immediate  action  of  antigens  on  the  organism  because  we 
have  no  idea  of  the  quantity  of  actual  antigen,  that  is  of  the 
really  active  substance  which  is  only  part  of  a  mixture  and 
which  we  cannot  extract  in  pure  state. 

For  example,  we  do  know  that  a  cubic  centimeter  of  a 
broth  culture  of  diphtheria  bacilli  contains  two  or  three  hun- 


30  THEORIES  OF  IMMUNITY 

dred  doses,  lethal  for  a  guinea-pig,  while  in  the  case  of  typhoid 
or  plague  2  or  3  c.c.  of  a  broth  culture  are  necessary  to  kill, 
but  we  do  not  know  to  what  quantity  of  active  substance  a 
fatal  dose  corresponds  nor  whether  typhoid  or  plague  bacilli 
produce  quantities  of  toxins  greater  in  the  organism  than  in 
artificial  cultures.  We  cannot  then  know  whether  typhoid 
or  plague  toxin  produces  on  the  organism  effects  analogous 
to  those  of  diphtheria  toxin  even  if  it  were  possible  to  obtain 
typhoid  and  plague  toxin  in  very  much  greater  concentration 
than  other  more  or  less  poisonous  substances  in  our  culture 
media. 

At  all  events,  however  much  we  can  judge  by  the  apparent 
results  of  present  experiments,  we  may  admit  that  the  prod- 
ucts of  the  secretions  of  certain  bacteria  as  well  as  certain 
other  antigens  may  exercise  a  direct  action  on  the  organism, 
while  in  the  case  of  other  bacteria  the  pathogenic  reaction 
manifests  itself  only  after  a  special  preparation — an  indirect 
action. 

Thus,  for  example,  we  know  that  the  toxins  of  diphtheria 
and  tetanus  act  quite  quickly  on  normal  tissues  while  tuber- 
culin, malein,  and  very  probably  also  the  secretion  of  the 
treponema  of  syphilis  do  not  act  under  the  same  conditions, 
but  only  on  infected  tissues  and  only  in  a  longer  or  shorter 
time  after  the  infection.  In  the  first  case  the  tissue  is  sus- 
ceptible without  preparation  of  any  sort;  in  the  other  it 
becomes  susceptible  only  after  a  specific  preparation.  The 
action  of  antigens  on  tissues  may  then  be  direct  or  indirect 
and  this  difference  can  be  determined  only  by  the  physico- 
chemical  properties  of  these  substances,  or  by  the  nature 
of  the  compounds  which  they  form  with  their  "normal  anti- 
bodies," or  finally,  by  the  biologic  properties  of  the  compounds 
thus  formed  which  may  be  neutral  or  more  or  less  pathogenic 
to  the  organism. 

In  order  to  fully  understand  the  first  stages  in  the  evolution 
of  a  disease  as  well  as  the  mechanism  of  the  defense  of  the 
organism,  the  question  of  the  infecting  dose  is  of  capital 
importance.  We  may  assume  that  no  antigen  is  exclusively 
pathogenic  as  none  is  exclusively  harmless.  We  can  always 
find  for  the  most  active  toxin  a  dose,  which  will  provoke  no 


THEORIES  OF  IMMUNITY  31 

appreciable  trouble  in  the  organism,  and  the  injection  of  the 
apparently  most  innocuous  albumin  will  disturb  the  normal 
equilibrium  whenever  a  certain  dose  is  exceeded. 

If  then  we  assume  with  Ehrlich  that  a  cell  can  be  attacked 
by  an  antigen  only  in  case  it  possesses  a  substance  (normal 
antibody)  which  has  a  special  chemical  affinity  for  that 
antigen,  and  if  we  complete  this  hypothesis  by  the  experi- 
mental fact  analyzed  above  under  the  name  of  "phenomenon 
of  surcharge'^  we  may  easily  explain  the  immunizing  and 
pathogenic  action  of  the  antigen.  This  action  will  be  exclu- 
sively immunizing  when  the  quantity  of  antigen  fixed  by  the 
cell  does  not  exceed  or  is  less  than  the  capacity  of  neutraliza- 
tion by  the  antibody;  it  will  be  pathogenic  when  a  quantity 
of  antigen  fixed  is  larger  than  the  neutralization  capacity. 
The  normal  functions  of  the  cells  will  then  be  disturbed  and 
they  will  suffer  more  or  less.  Experience  has  shown  that  we 
obtain  an  active  immunity  all  the  more  intense  and  all  the 
more  rapidly,  in  other  words,  we  obtain  a  quantity  of  "anti- 
body in  excess"  all  the  greater,  when  injections  are  restricted 
and  when  they  never  exceed  the  w^ell-tolerated  dose.  We 
may  say,  in  a  word,  that  immunization  will  be  always 
inversely  proportional  to  intoxication  or  that  the  quantity 
of  "antibody  in  excess"  will  be  directly  proportional  to  the 
intensity  of  the  immunizing  action  of  the  antigen. 

The  study  of  certain  infectious  diseases  will  permit  us  to 
better  define  our  thought.  Finally,  we  may  conclude  from 
what  precedes  that  every  pathologic  state  caused  by  an 
antigen  is  determined  by  the  reactions  which  this  antigen 
may  provoke  in  the  organism  and  that  the  nature  and  the 
gravity  of  these  reactions  must  necessarily  depend  upon: 

1.  The  affinities  of  the  antigen  for  some  other  substance 
intravascular  or  intracellular  in  the  organism. 

2.  The  nature  of  the  reactions  of  the  antigen  with  pre- 
existing, that  is  to  say,  normal  antibodies. 

3.  The  importance  of  the  role  which  the  antibodies  play 
in  the  life  of  the  cells  and  of  the  cells  in  the  organism. 

4.  The  nature  and  properties  of  the  compounds  which 
the  antigen  may  form  with  "antibodies  in  excess." 

Any  of  these  reactions  may  present  special  peculiarities 


32  THEORIES  OF  IMMUNITY 

in  each  pathologic  state.  It  will  be  necessary  to  analyze 
in  detail  a  certain  number  of  pathologic  states  caused  by 
different  antigens  in  order  to  study  their  differences  and 
their  common  characteristics.  We  will  begin  this  study  by 
the  analysis  of  the  action  on  the  organism  of  the  arseno- 
benzenes  because  we  know  the  chemical  composition  of  these 
substances.  We  will  continue  the  studies  by  a  series  of 
monographs  having  for  their  subjects  the  pathogenicity  and 
evolution  of  the  better  known  infectious  diseases:  diphtheria, 
tuberculosis,  typhoid  fever,  with  other  intestinal  infections 
and  septicemias  caused  by  various  parasites  such  as  plague, 
malaria  and  trypanosomiasis. 


I 


CHAPTER  II. 
PHYSICOCHEMICAL  PROPERTIES 

Transformations  of  the  Arsenobenzenes  "in  Vitro"  and  in  the  Organism. 

The  discovery  of  the  arsenobenzenes  and  especially  of 
their  physicochemical  and  biological  properties  has  opened 
new  horizons  for  the  study  of  the  transformation  of  anti- 
gens. It  has  been  recognized  that  certain  arsenobenzenes, 
more  particularly  arsenophenylglycin  and  dioxydiamino- 
arsenobenzene  (salvarsan)  or  its  compounds,  mono-  bi-  or 
trimetallic  luargol  or  cupriluargol  are  colloids  and  may 
cause  the  formation  of  specific  antibodies  under  the  same 
conditions  as  the  biologic  antigens  which  we  have  studied 
heretofore.  These  substances  possess  properties  essentially 
analogous  to  every  other  antigen.  Let  us  see  how  it  has  been 
possible  to  consider  them  in  this  way. 

The  product  which  has  been  most  particularly  studied 
from  this  pK)int  of  view  is  dioxydiaminobenzene-antimonious- 
silver-bromide  (luargol)  because  it  is  a  strongly  colored 
red-brown  solution  which  allows  us  to  follow  it  in  its  trans- 
formations much  easier  than  simple  arsenobenzene  or  arseno- 
phenylglycin, the  color  of  which  does  not  differ  essentially 
from  that  of  serum  or  other  organic  fluids.  Luargol  is  a 
yellow  powder  more  or  less  dark  colored,  insoluble  in  the 
basic  state  but  soluble  when  slightly  acidified  with  hydro- 
chloric, phosphoric  or  citric  acid;  insoluble  as  a  sulphate, 
but  soluble  as  a  sodium  compound  when  made  slightly 
alkaline. 

The  most  convenient  preparations  for  treatments  and 

experiments  are  the  sodium  compounds  and  monosodium 

or  disodium  solutions  can  be  obtained  as  well  as  intermediary 

'alkalies  between  these  two  limits  as  well  as  hyperalkaline 

solutions. 

When  intravenous  injections  of  these  different  alkaline 
3 


34  PHYSICOCHEMICAL  PROPERTIES 

solutions  are  given  to  a  series  of  animals,  the  apparent  toxicity 
of  these  products  diminishes  as  their  alkalinity  increases. 
Thus  the  rapid  intravenous  injection  of  5  eg.  of  m6no- 
sodium  luargol  will  kill  a  rabbit  in  a  few  minutes  while  an 
injection  of  40  eg.  of  the  same  disodium  product  or  a  little 
hyperalkaline  will  not  kill  the  rabbit.  Moreover,  it  is  not 
the  addition  of  the  soda  which  has  rendered  this  product 
less  toxic  because  monosodium  compounds  are  ordinarily  less 
toxic  than  the  disodium,  provided  the  injections  are  made 
in  minutes  rather  than  in  some  seconds. 

We  must  conclude,  therefore,  from  this  primary  series  of 
experiments  that  the  rapid  death  of  an  animal  by  no  means 
indicates  the  degree  of  toxicity  of  a  product  hut  this  rapid  death 
may  he  a  phenomenon  of  some  other  nature. 

In  order  to  understand  the  causes  of  this  rapid  death  it 
has  been  necessary  to  undertake  other  experiments  and 
especially  to  study  more  closely  the  physicochemical  proper- 
ties of  the  arsenobenzenes  as  well  as  the  transformations 
which  these  products  undergo  "in  vitro''  and  "in  vivo." 
When  we  seal  in  a  series  of  tubes,  various  solutions  of  sodium 
luargol  of  different  degrees  of  alkalinity  in  very  pure  distilled 
water  we  find  that  these  solutions  remain  for  a  long  time 
perfectly  clear  and  when  we  expose  them  to  the  air  and  to  the 
light,  they  undergo  no  alteration  for  several  minutes.  On 
the  other  hand,  if  instead  of  dissolving  these  products  in 
distilled  water  the  solutions  are  prepared  with  salt  solution 
(6  to  10  per  thousand  of  sodium  chloride)  we  find  that  the 
monosodium  compounds  precipitate  in  a  few  minutes;  the 
disodium  in  a  few  hours;  the  hyperalkaline  in  a  few  days. 
Other  salts,  especially  those  of  calcium  are  still  more  active 
in  this  regard. 

The  rapidity  with  which  a  precipitate  is  formed  in  vitro 
in  salt  mixtures  coincides  perfectly  with  the  apparent  toxicity 
of  the  solutions  and  when  an  autopsy  is  made  on  an  animal 
which  has  succumbed  in  a  few  minutes  to  a  large  dose  of  one 
of  these  solutions,  precipitates  are  easily  found  in  the  heart 
and  in  the  pulmonary  vessels  as  well  as  numerous  infarcts  in 
all  the  tissues  and  organs.  (Ch.  Fleig,  "Toxicite  du  Sal- 
varsan.") 


PHYSICOCHEMICAL  PROPERTIES  35 

What  makes  us  hesitate  to  assume  that  the  precipitant 
action  is  the  only  cause  of  death,  is  that  we  may  kill  the  test 
animal  by  relatively  small  doses  of  the  product  and  under 
these  conditions,  although  infarcts  are  found  at  autopsy, 
intravascular  precipitates  are  never  found.  Furthermore, 
solutions  of  luargol  in  serum  or  in  salt  solution  added  to 
normal  serum  retain  their  clarity  longer  than  in  pure  dis- 
tilled water.  It  seems  certain  that  if  the  precipitate  is  not 
found  in  serum  it  is  only  because  of  the  difficulty  of  demon- 
strating it  and  if  serum  does  not  precipitate  luargol  in  vitro, 
it  is  because  it  has  lost  the  salts  which  play  the  greatest  role 
in  the  formation  of  the  precipitate  and  which  are  retained 
by  the  coagulum,  and  because  albumins  prevent  precipita- 
tion of  colloids. 

In  fact  when  instead  of  treating  the  solution  of  luargol 
with  serum  it  is  treated  with  fresh  whole  blood  recently 
drawn  from  the  carotid  and  when  after  violently  shaking 
and  centrifuging  the  mixture,  the  parts  are  analyzed  sepa- 
rately, much  more  luargol  is  found  in  the  sediment  than  in 
the  supernant  fluid  and  microscopic  examination  of  the 
sediment  shows  finely  granular  viscous  masses. 

To  sum  up,  one  may  assume  with  certainty  that  the  rapid 
death  of  experimental  animals  caused  by  the  sudden  injec- 
tion of  monosodium  preparations  is  caused  only  by  the  pre- 
cipitate which  fills  the  capillaries  and  thus  produces  con- 
gestion and  infarcts  in  different  parts  of  the  organism.  The 
symptoms  observed:  dyspnea,  congestion  of  the  mucous 
membranes,  epileptiform  convulsions,  gastro-intestinal  dis- 
turbances, fall  of  blood-pressure,  subnormal  temperature 
are  identical  to  those  symptoms  which  are  observed  in  the 
phenomenon  of  "anaphylactic  shock."  The  explanation 
of  the  mechanism  of  the  reaction  and  of  the  crisis  which 
results  from  it,  is,  in  these  cases,  easy  and  simple.  We  have 
seen  that  the  arsenobenzenes,  soluble  in  the  state  of  di-  or 
even  monosodium  salts,  are  insoluble  as  neutral  bases. 
The  weakest  acids  replace  the  sodium  of  the  sodium  com- 
pounds. Consequently  when  injected  into  the  blood  the 
compound  loses  its  sodium  by  reason  of  the  carbonic  and 
other  organic  acids  of  Ithe  plasma,  and  becomes  insoluble. 


36  PHYSICOCHEMICAL  PROPERTIES 

It  is  then  evident  that  the  monosodium  compounds  will  be 
much  more  easily  and  rapidly  transformed  to  bases  than  the 
disodium  or  hyperalkaline  compounds. 

But  as  the  monosodium  compounds  cause  crises  only  when 
injected  rapidly  and  do  not  produce  them  when  injected 
slowly,  we  can  draw  logically  this  third  conclusion,  that,  if 
the  formation  of  the  precipitate  is  the  primary  cause,  the 
origin  and  the  intensity  of  the  disturbance  is  determined  only 
by  the  duration  of  the  reaction.  And  to  this  conclusion 
Doerr,  Besredka,  Mutermilch,  and  others,  have  come  in 
order  to  explain  anaphylactic  shock  as  caused  by  biologic 
antigens.    Thus  we  see : 

1.  That  intravenous  injections  can  cause  immediate  dis- 
turbance. 

2.  That  this  disturbance  arises  by  the  transformation  of  a 
soluble  sodium  compound  to  an  insoluble  base,  that  is  to  say, 
to  a  precipitate. 

3.  That  the  degree  of  the  disturbance  is  caused  by  the 
rapidity  with  which  the  reaction  takes  place. 

And  we  may  therefore  conclude  that  death  or  non-fatal 
crisis  which  immediately  follows  injection  is  determined  by 
a  reaction  which  is  exclusively  intravascular;  that  it  does  not 
result  from  any  toxic  reaction  of  the  product  but  from  its 
mechanical  action  on  the  capillary  circulation. 

Moreover,  this  is  not  the  only  expfanation  which  can  be 
given  to  this  phenomenon.  The  reactions  of  the  organism, 
however  localized  they  may  be,  are  never  simple.  The 
arsenobenzenes  can  be  combined  with  a  series  of  other  sub- 
stances which  exist  in  the  blood  plasma  and  especially  with 
the  calcium  salts  and  can  thus  form  compounds  which  are 
more  or  less  insoluble.  By  removing  these  substances  from 
the  blood  the  injection  causes  a  rupture  of  equilibrium  and 
especially  a  modification  of  plasma  coagulability  which 
necessarily  reacts  on  the  intracellular  fluids.  The  purely 
mechanical  intravascular  action  of  emboli  may  therefore  be 
complicated  by  intimate  and  complex  intracellular  reactions 
as  in  the  case  of  biologic  antigens.  And  in  this  case  also,  it 
is  the  factor  ''time,"  the  rapidity  of  the  reaction,  which  plays 
the  principal  role  in  the  severity  of  pathologic  manifestations. 


PHYSICOCHEMICAL  PROPERTIES  37 

The  first  stage  of  the  transformation  which  the  sodium 
compounds  of  the  arsenobenzenes  undergo  in  the  organism 
consists  then  in  making  them  change  from  the  soluble  state 
to  the  insoluble  state.  They  form  precipitates  or  coagula 
in  the  interior  of  vessels  and  these  then  provoke  disturb- 
ances which  are  more  or  less  severe  according  to  the  in- 
jected dose,  the  degree  of  alkalinity  of  the  product,  or  what 
amounts  ultimately  to  the  same  thing,  to  the  quantity 
variable  from  one  individual  to  another,  of  precipitating 
substances  which  preexist  in  the  blood:  Other  conditions 
being  the  same,  the  reaction  will  depend  also  upon  the  rapid- 
ity with  which  the  injection  is  made. 

There  is  thus  a  primary  analogy  between  the  action  of 
the  arsenobenzenes  and  of  biologic  antigens  and  for  greatet- 
convenience  in  the  discussion  which  follows  we  may  call 
the  disturbances  which  immediately  follow  the  injection 
primary  intravascular  disturbances  and  we  may  group  the 
total  of  substances  in  the  organism  which  concur  in  the  forma- 
tion of  the  precipitate  under  the  name  of  preexisting  or  normal 
antibody  (and  we  know  that  in  this  case,  these  include  acids 
and  salts,  sodium  chloride,  calcium  phosphate,  etc.) 

Arsenobenzene  which  becomes  insoluble  in  the  blood 
plasma  does  not  remain  indefinitely  in  the  organism  in  the 
precipitated  state.  We  may  assume  that  only  one  part  of 
the  injected  product  becomes  insoluble;  another  part  remains 
in  solution  or  passes  to  the  precipitated  state  only  after  a 
very  short  time,  a  fraction  of  a  second. 

In  fact  when  we  inject  an  animal  intravenously  with  a 
series  of  small  doses  of  luargol,  we  obtain  after  a  certain 
incubation  period  a  serum  w^hich  precipitates  luargol  of  the 
same  alkalinity  in  vitro.  But  at  the  same  time  we  know  as  a 
result  of  seeking  to  define  the  conditions  of  the  formation  of 
this  precipitate,  that  the  reaction  is  not  simple;  whatever 
may  be  the  proportions  of  sera  and  luargol  in  mixtures,  total 
coagulation  of  the  latter  is  never  obtained.  It  is  found,  further- 
more, that  in  certain  mixtures  the  precipitate  already  formed 
redissolves  in  some  minutes  or  some  hours  afterward. 

In  order  to  explain  the  cause  of  the  particular  nature  of 
all  these  reactions,  we  must  remember  these  facts:   That  in 


38  PHYSICOCHEMICAL  PROPERTIES 

a  serum  there  are  both  acid  functions  and  alkaline  functions 
in  unstable  equilibrium  which  may  act  more  or  less  rapidly 
on  disodium  luargol.  That  luargol  is  soluble  in  the  mono- 
and  disodium  state  and  also  in  the  state  of  a  mono-  and  di- 
acid  compound  (hydrochloric,  phosphoric  or  citric);  and 
that  in  the  presence  of  the  salt  contained  in  the  blood  the 
"mono"  compounds  precipitate  more  easily  than  the  diacid 
or  dialkaline  compounds. 

The  acid  function  acts  first  because  there  is  in  serum  a 
little  free  carbonic  acid  which  precipitates  one  part  of  the 
luargol  as  a  base  but  soon  afterward  it  is  the  alkaline  function 
which  appears  to  hinder  the  coagulation  of  the  part  which 
still  remains  in  solution,  and  even  to  redissolve  a  part  of  the 
precipitate  already  formed.  In  case  the  serum  is  hyperacid, 
the  precipitate  will  not  form  because  certain  acid  compounds 
of  luargol  are  soluble. 

It  is  important  to  note  that  this  state  of  equilibrium 
between  the  acid  and  alkaline  functions  may  be  different  in 
the  serum  of  each  normal  animal,  whether  prepared  by  one 
or  several  previous  injections.  The  formation  of  a  heavier 
precipitate  in  the  sera  of  prepared  animals  would  indicate  a 
temporary  predominance  of  the  acid  function  or  the  presence 
of  a  larger  quantity  of  substances  which  form  with  the  arseno- 
benzenes,  compounds  less  soluble  (lime  salts,  etc.),  or,  what 
is  more  probable,  the  two  factors  at  once. 

Heating  to  60°  or  65°  has  the  effect  of  stabilizing  or  fixing 
the  acid  and  alkaline  functions  of  serum  and  rendering  it 
neutral  toward  luargol.  By  adding  acid  to  such  a  serum  it 
is  possible  to  reactivate  this  precipitate  again;  by  adding 
sodium  one  reactivates  the  solvent  action.  By  treating  in 
this  way  a  serum  normally  neutral,  whether  heated  or 
unheated,  we  find  that  when  heated  in  order  to  give  us  a 
precipitate  more  acid  is  needed  and  in  order  to  redissolve, 
more  alkali  than  in  unheated  serum. 

So  much  of  the  chemical  constitution  of  serum  and  anti- 
body remains  unknown  that  it  will  be  hardly  possible  for  us 
to  grasp  an  exact  idea  of  the  chemical  mechanism  of  these 
reactions.  The  key  to  the  problem  lies  in  researches  of  this 
.kind  in  which  the  composition  of  one  of  the  elements  of  the 


PHYSICOCHEMICAL  PROPERTIES  39 

reaction  is  exactly  known.  For  the  moment  it  seems  to  us 
important  to  recall  the  complete  identity  of  the  reactions 
between  serum  and  arsenobenzene  on  the  one  hand  and 
between  serums  and  biologic  antigens  (albumins,  microbes 
and  their  secretions)  on  the  other. 

In  fact  it  is  more  than  probable  that  in  the  two  cases  the 
nature  and  the  mechanism  of  the  reactions  are  the  same.  It 
is  the  reaction  of  the  acid  and  the  alkaline  functions  of  the 
antibody,  favored  by  the  chlorides  and  phosphates  of  sodium 
and  calcium  as  well  as  certain  substances,  such  as  lipoids, 
lecithin,  cholesterin,  which  cause  coagulation  or  dissolution 
of  the  antigen;  the  action  of  the  acid  and  alkaline  function 
ought  to  be  fundamental  and  always  the  same.  Thus  should 
be  explained  complement  or  alexine  which  is  found  indiffer- 
ently in  every  normal  serum,  which  disappears  on  heating  and 
which  can  reactivate  the  action  of  a  specific  serum  antibody 
when  this  is  heated.  Specific  precipitant  action  should  be 
determined  by  the  salts  of  calcium  and  other  substances  in 
the  plasma  which  form  with  arsenobenzenes,  more  stable, 
less  soluble  combinations  of  which  the  quantity  increases 
as  the  result  of  a  series  of  injections.  Thus  should  be 
explained  the  sensitizing  substances  or  amboceptors  which  do 
not  disappear  on  heating,  which  combine  with  antigen,  but 
whose  action  must  be  assisted  first  by  acids  and  oxidizing 
agents,  finally  by  alkalies  in  order  to  become  appreciable. 

Dioxydiaminoarsenobenzene  has  several  afiinities.  Tri- 
valent  arsenic  can  fix  two  molecules  of  metallic  salts;  amines 
can  be  bound  by  acids  or  by  formic  aldehyde  and  through 
this  latter  can  fix  a  series  of  other  substances.  The  oxyhy- 
drate  radicals  may  exchange  their  hydrogens  for  a  series  of 
inorganic  or  organic  bases.  We  know  for  example  that  when 
one  binds  to  the  amines  of  arsenobenzene  one  or  two  molecules 
of  formaldehyde  sulphonate  of  sodium,  the  product  becomes 
soluble  in  neutral  medium  and  passes  from  the  colloidal 
state  to  the  state  of  a  salt  and  that  by  the  substitution  for 
the  hydrogen  of  the  oxyhydrate  radical  one  may  make  these 
combinations  soluble  with  salts  of  calcium. 

A  non-lethal  dose  of  luargol  injected  into  the  blood  of  an 
animal  in  the  form  of  a  sodium  compound  ought  then  to 


40  PHYSICOCHEMICAL  PROPERTIES 

undergo  a  series  of  successive  transformations  without  the 
whole  of  the  injected  product  ever  being  able  to  take  part 
simultaneously  in  each  of  the  reactions  which  follow.  We 
may  outline  this  transformation  in  a  schematic  method  as 
follows : 

1.  One  part  of  the  injected  product,  the  more  colloidal, 
combines  with  the  calcium  salts,  loses  its  sodium  and  thus 
becomes  rapidly  an  insoluble  base  of  which  one  part  continues 
to  circulate  in  the  blood,  while  the  other  part  is  taken  up  by 
leukocytes  in  the  liver,  the  spleen,  the  lymphatic  glands  and 
finally  in  the  local  lesions  which  become  the  site  of  an  inflam- 
matory process  at  the  point  of  injection. 

2.  Another  part  of  the  product  is  not  precipitated  and 
continues  to  circulate  in  the  blood  as  a  sodium  compound. 
This  is  probably  the  least  colloidal  part.  It  can  traverse 
certain  membranes  and  thus  penetrate  to  the  interior  of  cells 
where  it  is  fixed  as  a  base;  that  is  to  say,  as  a  new  insoluble 
compound. 

3.  A  third  part  finally  becomes  rapidly  and  almost  simul- 
taneously a  base  and  a  salt  and  as  such  may  be  partially 
assimilated,  that  is  to  say,  fixed  by  certain  cells,  partially 
eliminated  by  the  kidneys  and  intestines.  In  point  of  fact, 
some  minutes  after  the  injection,  traces  of  arsenobenzene 
are  found  in  the  urine,  to  be  sure  in  a  soluble  state,  because 
when  one  adds  directly  to  the  same  urine  a  little  of  the 
same  solution  of  arsenobenzene  there  immediately  forms  an 
abundant  precipitate.  The  product  has  thus  passed  into  the 
urine  in  the  form  of  a  compound  which  is  no  longer  precipi- 
tated by  salts. 

The  proportion  of  the  product  which  is  either  engulfed  by 
leukocytes  as  a  precipitate,  or  which  continues  to  circulate 
in  the  blood  as  a  precipitate  or  which  passes  out  and  precipi- 
tates in  the  cells  of  different  tissues  as  a  colloidal  solution  or 
as  a  salt  and  finally  the  proportion  which  is  immediately 
eliminated,  vary  widely  according  to  the  injected  doses, 
the  degree  of  alkalinity  of  the  product,  and  the  composition 
of  the  blood  of  the  injected  animal  at  the  time  of  the  primary 
injection  (or  later  if  injections  are  made  in  series).  Thus 
symptoms  may  vary  infinitely. 


PHYSICOCHEMICAL  PROPERTIES  41 

Experiments  with  doses  of  arsenic  made  by  Mile.  Michel 
(by  the  method  of  Bougault)  have  given  the  following 
results. 

Experiment  1.— The  whole  blood  of  a  rabbit  bled  white 
is  added  to  10  eg.  of  luargol  in  a  solution  of  10  c.c.  of  distilled 
water,  is  shaken  violently  to  prevent  coagulation  and  allowed 
to  stand  for  twenty-four  hours.  The  fluid  is  centrifuged  and 
38  c.c.  of  dark  liquid  and  30  c.c.  of  precipitate  are  obtained 
in  which  are  found : 

Arsenic,  mg. 

In  the  fluid 4.62 

In  the  precipitate 15.37 

in  all  the  same  20  mg.  of  arsenic  contained  in  the  10  eg.  of 
luargol  of  which  about  one-quarter  remains  in  solution  in 
the  serum  and  the  other  three-quarters  have  been  partly 
fixed  by  the  formed  elements  of  the  blood  and  partly  pre- 
cipitated as  finely  granular  viscous  masses.  Only  a  very 
small  quantity  of  coagulated  fibrin  is  formed. 

Experiment  2.— A  rabbit  is  injected  intravenously  with 
10  eg.  of  luargol  dissolved  in  10  c.c.  of  distilled  water  and  is 
bled  twenty-four  hours  afterward.  At  the  same  time  the 
urine  for  the  twenty-four  hours  is  collected  and  is  added  to 
the  feces  as  well  as  to  the  intestinal  contents  after  the  bleed- 
ing.   The  blood  is  centrifuged  and  we  find : 

In  55  c.c.  of  coaguium  about  1 . 0  mg.  of  arsenic  ^  •?  r 

In  37  c.c.  of  serum  2.5        "  "  r<*omg. 


In  275  c.c.  of  urine  2.3 

In  90  gr.  of  fecal  matter  3 . 2 


5 . 5  mg. 


which  means  that  a  little  more  than  a  quarter  of  the  injected 
luargol  has  been  eliminated  in  twenty-four  hours  by  the 
kidneys  and  intestines;  about  one-eighth  remains  in  the 
serum  as  un  transformed  luargol  and  one-sixteenth  has  been 
absorbed  and  fixed  in  the  elements  of  the  circulating  blood  at 
the  moment  of  bleeding.  In  estimating  at  10  per  cent,  the 
quantity  of  blood  remaining  in  the  vessels,  we  may  assume 
that  after  twenty-four  hours  approximately  one-half  of  the 
luargol  originally  injected  has  remained  fixed  in  the  organs 
or  tissues. 


42  PHYSICOCHEMICAL  PROPERTIES 

By  comparing  the  doses  of  this  second  experiment  with 
those  of  the  first,  that  is  to  say,  by  recognizing  the  large 
proportion  (three-quarters)  of  luargol  fixed  by  the  cells  of 
the  blood  in  a  mixture  in  vitro  and  the  very  small  proportion 
(one-sixteenth)  found  in  the  coagulum  in  the  injected  rabbit 
twenty-four  hours  after  the  injection,  we  may  assume  that 
the  largest  part  of  the  luargol  remaining  in  the  organism  has 
been  fixed  by  other  elements,  probably  by  leukocytes  and 
transported  to  the  liver,  spleen,  and  to  the  hemopoietic 
organs. 

By  estimating  the  arsenic  eliminated  day  by  day  following 
a  single  injection,  Mile.  Michel  found  in  certain  cases  traces 
of  arsenic  in  the  urine  twenty-four  days  after  the  injection 
of  a  dose  of  10  eg.  in  a  rabbit  weighing  2500  gm.  In  these 
cases  the  elimination  is  not  regular  but  takes  place  by  suc- 
cessive discharges  (Emery  and  Jeanselme)  at  intervals  of 
three,  four  or  even  eight  days.  The  largest  quantity  is 
eliminated  in  the  first  sixty  hours.  By  estimating  the  total 
quantity  of  eliminated  arsenic,  we  find  that  up  to  some 
tenths  of  a  milligram,  the  organism  retains  none  of  an  arsenic 
compound  injected  as  luargol. 

In  man  therapeutic  doses  of  luargol  exactly  disodic  (5  to 
30  eg.)  never  provoke  primary  reactions  but  very  small  doses 
of  5  to  10  eg.  may  produce  a  slight  reaction  of  another  nature, 
rarely  in  two  to  three  hours,  generally  in  twelve  to  twenty- 
four  hours  after  the  injection.  These  reactions  are  mani- 
fested generally  only  after  the  first  injection  and  consist  of  a 
mild  and  transient  fever  (38°  to  38.5°  C.)  for  one  to  two  hours 
accompanied  sometimes  by  chills  and  mild  headache,  very 
rarely  by  nausea  and  diarrhea,  corresponding  to  the  fixation 
of  the  product  by  the  cells.  The  nature  of  the  symptoms 
leads  us  to  suppose  principally  a  reaction  of  the  cells  of  the 
central  nervous  system. 

There  is  not  generally  a  reaction  to  the  second  injection 
nor  to  following  injections  even  if  the  doses  are  progressively 
increased  because  as  we  have  seen  above  the  elimination  of 
the  product  is  very  slow  so  that  each  of  the  successive  doses 
may  be  considered  as  a  preparation  or  vaccination  for  the 
following  injection.    There  is  even  a  sort  of  tolerance  or  a 


PHYSICOCHEMICAL  PROPERTIES  43 

cellular  immunity  identical  to  that  which  is  observed  to 
toxins  and  other  biologic  antigens.  Cells  multiply  their  anti- 
bodies and  may  transform  larger  and  larger  quantities  of 
antigen  (up  to  a  certain  limit)  without  being  disturbed  in 
their  normal  functions. 

Thus  as  far  as  it  is  possible  to  judge  by  repeated  daily 
analyses  of  urine  and  intestinal  contents,  of  blood,  organs 
and  tissues  in  a  series  of  animals  from  the  time  of  injection 
to  the  total  elimination  of  the  injected  product,  we  may 
assume  that  arsenobenzene  injected  into  the  blood  as  a 
soluble  colloid  passes  partially  as  a  precipitate  into  the 
organs  (liver,  spleen,  etc.)  and  partially  as  a  solution  into  the 
cells  of  different  tissues  where  it  becomes  insoluble.  That 
part  fixed  by  organs  and  tissues  is  transformed  either  into 
soluble  crystalloids  which  again  pass  into  the  blood  and  are 
eliminated  by  the  kidneys  and  intestines,  because  they  have 
no  longer  any  affinity  for  the  contents  of  the  cells,  or  into 
soluble  semi-colloidal  products  which  also  pass  into  the 
circulation  but  may  again  be  fixed  by  the  cells  to  be  finally 
transformed  into  neutral  salts  and  eliminated  as  such.  Some 
of  the  injected  arsenobenzene  is  transformed  directly  in  the 
blood  to  a  neutral  salt  which  is  rapidly  eliminated  without 
passing  through  the  tissues.  It  is  this  last  portion  which 
forms  the  primary  discharges  of  the  product  eliminated  in 
the  first  twenty-four  hours  and  which  marks  the  first  summit 
of  the  elimination  curve.  The  second  summit  which  is 
generally  ended  on  the  third  or  fourth  day  after  the  injection 
indicates  the  second  discharge  of  the  product  which  has  been 
fixed  and  dissolved  in  the  organs  and  tissues.  Little  summits 
which  are  noted  up  to  the  tenth  and  thirteenth  day  corre- 
spond to  little  successive  discharges  of  the  product  which 
have  once  or  twice  been  refixed  and  redissolved  in  the  tissues. 

Summary.— Arsenobenzene  is  an  arseniated  or  arseno- 
antimonious  or  multimetallic  amine  which  in  the  form  of  a 
sodium  compound  does  not  exist  as  a  free  molecule  but  whose 
component  molecules  in  greater  or  less  number,  form  col- 
loidal granules.  When  injected  into  the  blood,  the  colloidal 
granule  passes  through  a  series  of  transformations  which 
lead  to  its  disintegration  and  to  the  liberation  of  its  molecules. 


44  PHYSICOCHEMICAL  PROPERTIES 

From  the  physical  point  of  view  the  transformation  consists 
of  a  series  of  successive  passages  from  the  state  of  colloidal 
solution  to  the  state  of  coagulum  and  from  this  latter  to  the 
state  of  crystalloid  solution. 

From  the  chemical  yoint  of  view,  judging  by  experiments  in 
vitro  the  disintegration  of  colloids  and  the  liberation  of  mole- 
cules takes  place  by  a  binding  of  amines  and  the  fixation  of 
bases  by  oxyhydrate  radicals. 

From  the  physiological  point  of  view,  the  formation  of 
coagula  may  cause  intravascular  and  intracellular  disturb- 
ances because  in  the  blood,  the  reactions  are  rapid  and  sud- 
den. In  the  interior  of  cells  reactions  may  be  also  violent 
but  take  place  only  after  a  longer  or  shorter  incubation 
period. 

When  at  the  end  of  these  transformations,  the  molecule 
of  arsenobenzene  has  fixed  to  itself  substances  for  which  it 
has  an  affinity,  it  becomes  neutral  for  the  organism  and  is 
eliminated. 

In  a  word,  the  processes  are  of  exactly  the  same  sequence  and 
of  the  same  nature  as  those  which  an  albumin  undergoes  when 
submitted  to  digestion. 

Digestion  has  no  other  effect  than  to  liberate  molecules  of 
amino  acids.  By  certain  substitutions  of  unsatisfied  bonds, 
these  molecules  are  rebound  by  certain  lateral  chains  to  form 
colloidal  aggregates.  It  is  very  probable  that  these  chains 
which  vary  infinitely,  constitute  the  specificity  of  albumins 
and  of  antigens  in  general  and  that  antibodies  are  thus  noth- 
ing else  than  the  substances  of  the  organism  which  replace 
the  chains  and  bind  the  affinities  of  the  amino  groups. 


CHAPTER  III. 
EVOLUTION  OF  THE    INFECTIOUS  DISEASES. 

DIPHTHERIA. 

When  one  injects  a  non-fatal,  but  at  the  same  time,  a 
highly  pathogenic  dose  of  diphtheria  toxin  under  the  skin  of 
a  guinea-pig  one  sees  a  large  edema  develop  at  the  site  of 
injection  four  to  six  hours  afterward.  From  this  edema  and 
at  this  time,  almost  all  the  injected  toxin,  can  be  extracted. 
The  edematous  fluid  injected  into  a  second  guinea-pig  will 
produce  the  same  effect  as  the  toxin  injected  into  the  first. 
After  a  maximum  development  which  is  reached  at  the  third 
day,  the  edema  is  resorbed  little  by  little  and  finally  disappears 
at  the  end  of  fifteen  to  twenty  days.  The  quantity  of  toxin 
which  may  be  extracted  diminishes  at  the  same  time. 

When  this  edema  is  allowed  to  develop  normally  we  will 
find  from  the  center  to  the  periphery  every  degree  of  reaction 
which  toxin  can  produce  on  the  cellular  tissues  of  the  guinea- 
pig.  At  the  center  the  most  concentrated  solution  will 
destroy  the  cells;  there  will  be  necrosis  of  the  epidermis  and 
even  of  the  dermis  and  the  area  will  be  marked  by  an  eschar ; 
at  the  periphery  where  the  limit  is  marked  by  pallor,  the 
tissue  will  appear  normal.  When  we  try  to  produce  the 
Schick  reaction  at  the  site  occupied  by  the  edema  after  the 
complete  subsidence  of  the  latter,  we  find  that  the  zone 
limited  by  the  pallor  neutralizes  more  of  the  toxin  than  the 
central  part  formerly  occupied  by  the  eschar  and  more  than 
every  other  part  of  the  animal's  skin.  The  center  of  the 
area  previously  occupied  by  edema  will  give  a  positive  reac- 
tion to  a  dose  which  gives  a  negative  reaction  on  the  per- 
iphery. That  is  to  say,  there  is  a  local  immunity  at  the  site 
of  the  injection  of  the  toxin  and  this  immunity  is  most 
marked  at  the  site  which  has  suffered  least  by  the  injection. 


46       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

This  fact  agrees  with  the  observation  of  L.  Martin^  that  in 
mild  cases  of  disease  immunity  is  estabHshed  more  rapidly 
than  in  severe  cases. 

We  may  thus  consider  as  proved : 

1.  That  a  certain  pathogenic  dose  of  diphtheria  toxin  is 
fixed  by  the  cellular  tissues  of  the  guinea-pig  and  that  it  is 
retained  in  place  eight  or  ten  days  without  being  either 
neutralized  or  transformed. 

2.  That  immunization  or,  in  other  words,  the  excess  pro- 
duction of  the  "normal  antibody"  is  inversely  proportional 
to  the  intensity  of  the  reaction  and  to  the  gravity  of  the 
lesion. 

These  facts  which  do  not  accord  with  the  theory  of  Ehrlich 
are  very  easily  explained  in  the  light  of  experiments  con- 
cerning the  nature  and  properties  of  mixtures  of  toxins  and 
antitoxins.  We  have  seen  in  fact^  that  diphtheria  and  tetanus 
antitoxins  as  well  as  antiricin  can  ^x  their  toxins  en  surcharge; 
that  is  to  say,  in  a  quantity  greater  than  they  can  neutralize. 

The  passage  into  the  wash  water  of  tetanus  toxin  fixed 
en  surcharge  by  the  nervous  tissue  in  vitro^  as  well  as  the 
toxicity  of  the  edematous  fluid  in  the  experiment  above  are 
explained  very  simply  in  the  following  manner: 

Normal  antibody  contained  in  the  nervous  cells  or  in  the 
cellular  tissue  (diphtheria  in  a  guinea-pig,  horse  or  man)  can 
neutralize  a  definite  quantity  of  toxin.  The  product  of  this 
combination  is  neutral  for  the  cell  and  if  the  quantity  does 
not  exceed  its  digestive  capacity,  the  cell  digests  it,  eliminates 
it  and  reproduces  the  substance  neutralized  in  a  little  larger 
quantity  than  it  normally  contained.  The  cell  will  then  be 
capable  of  neutralizing  and  digesting  without  difficulty  a 
larger  quantity  of  toxin.  In  this  way  it  will  establish  a 
certain  local  immunity  and  the  tissue  so  immunized  will  give 
a  Schick  reaction  negative  for  a  dose  of  toxin  which  otherwise 
would  give  a  positive  reaction.  But  we  have  seen  that  the 
rwrmal  antibody  can  fix  more  toxin  than  it  can  neutralize 

1  Bull,  med.,  1917,  10  fevrier. 

2  Danysz,  J. :     Les  proprietes  et  la  nature  des  melanges  de  toxines  avec 
leurs  antitoxines,  Ann.  dc  I'lnst.  Pasteur,  mai,  1902. 

'  Danysz,  J.:     L'etude  de  Taction  de    la    toxine  tetaniquc  sur  la   sub- 
stance nerveuse,  Ann.  d.  I'lnst.  Pasteur,   1899,  p.   15f). 


DIPHTHERIA 


47 


and  the  more  it  fixes,  the  more  difficult  it  is  for  the  cell  to 
transform  and  eliminate  the  compounds  thus  formed.  The 
cell  may  then  succumb  to  the  task,  that  is  to  say,  to  a  veri- 
table indigestion  and  may  even  become  incapable  of  repro- 
ducing antibodies  in  excess. 

It  is  useless  to  complicate  the  problem  by  assuming  with 
Ehrlich  the  existence  in  every  toxin  of  a  haptaphore  group 
which  is  exclusively  immunizing  and  of  a  toxophore  group 
which  is  exclusively  pathogenic,  but  we  may  certainly  con- 
clude from  what  precedes  that  the  same  substance  will  cause 
one  or  the  other  of  these  reactions  following  doses  measured 
according  to  the  degree  of  sensitiveness  of  the  animal,  that, 
in  a  word,  the  immunizing  or  pathogenic  reaction  is  a  func- 
tion of  quantity  and  not  of  quality. 

We  may  represent  the  process  which  can  go  on  in  the 
edematous  tissues  of  the  above  experiment  according  to  the 
following  scheme: 


'AT    ANTIBOOV 

T.     TOXIN 

T,  toxin;  AT,  antitoxin.  1,  'pathogenic  compound;  the  antibody  is 
surcharged  with  toxin;  2,  3,  intermediate  compounds;  4,  non-pathogenic 
compound;  the  antibody  has  fixed  the  quantity  of  toxin  necessary  only 
to  produce  an  immunizing  reaction. 

Between  the  two  extremes,  all  intermediary  steps  are 
possible  but  the  quantity  of  toxin  which  an  antibody  can  fix 
en  surcharge  is  not  boundless  and  certain  facts  lead  us  to 
suppose  that  this  faculty  of  a  tissue  to  fix  larger  or  smaller 
quantities  of  antigen  depends  not  only  on  the  local  condition 
of  this  tissue  but  rather  on  the  general  state  of  the  organism. 
Thus  a  dose  of  toxin  fatal  for  a  guinea-pig  in  three  or  four 
days  will  produce  on  the  second  day  an  edema  less  volu- 


48       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

minous  than  a  non-fatal  dose.  A  dose  fatal  in  thirty-six  to 
forty-eight  hours  will  not  produce  edema  at  all.  We  must 
assume  first  that  the  cellular  tissue  can  retain  only  a  maximum 
of  toxin  beyond  which  the  excess  will  be  fixed  by  other  tis- 
sues more  vital  to  the  life  of  the  animal  and  second,  that  this 
general  reaction  of  nervous  origin  influences  the  local  reaction 
by  diminishing  the  fixation  capacity  of  the  cutaneous  cellular 
tissue. 

There  is  no  doubt  but  that  all  these  reactions  depend  upon 
physicochemical  affinities  and  if  we  do  not  know  the  exact 
mechanism  we  can  at  least  say  for  the  present  that  toxins 
as  well  as  antitoxins  are  colloidal  substances,  are  aggregates 
of  molecules  of  varying  size,  and  as  seen  in  the  ultramicro- 
scope  are  spherical  in  form.  We  know  that  when  causing  toxins 
and  antitoxins  to  dialyze  across  collodion  or  gelatin  mem- 
branes of  greater  or  less  density,  toxins  pass  easier  than  anti- 
toxins, from  which  we  can  conclude  that  toxins  form  aggre- 
gates less  voluminous  than  antitoxins.  The  recognition  of 
these  facts  is  sufficient  for  the  moment  to  explain  the  curious 
properties  of  mixtures  of  toxins  with  their  antitoxins  which 
we  have  noted  above. 

In  a  rabbit  treated  by  diphtheria  toxin,  the  phenomena 
observed  are  quite  different  from  those  in  the  guinea-pig. 
Hypodermic  injections  provoke  only  a  little  redness  at  the 
point  of  inoculation  and  if  the  dose  is  not  speedily  fatal  the 
rabbit  succumbs  almost  always  some  weeks  afterward  to  a 
cachexia  accompanied  by  nervous  disturbances.  In  this 
animal,  the  toxin  is  not  retained  in  the  cellular  tissue,  but 
passes  to  the  nervous  tissue  and  produces  disturbances  which 
are  relatively  much  more  severe.  The  same  result  may  be 
obtained  in  the  guinea-pig  by  injecting  a  mixture  of  toxin  and 
antitoxin  containing  a  slight  excess  of  toxin  or  of  toxin  fixed 
en  surcharge.  In  this  case  the  toxin  fixed  by  antitoxin  (in 
vitro)  is  retained  to  a  less  extent  by  cellular  tissue;  it  diffuses 
into  other  regions  of  the  organism  and  may  produce  in  the 
guinea-pig  the  same  cachectic  state  and  the  same  nervous 
disturbances  as  toxin  of  itself  produces  in  the  rabbit. 

The  susceptibility  of  man  seems  to  be  intermediary  between 
that  of  the  guinea-pig  and  that  of  the  rabbit.    In  man  toxin 


DIPHTHERIA  49 

is  fixed  by  the  cellular  tissue  but  may  also  be  fixed  by  nervous 
tissue.  The  preventive  vaccination  of  children  by  mixtures 
of  toxin  and  antitoxin  may  have,  as  noted  by  L.  Martin^ 
consequences  which  are  disagreeable  if  not  serious.  The 
susceptibility  of  the  horse  is  intermediary  between  that  of 
man  and  of  the  guinea-pig.  In  a  horse  treated  by  diphtheria 
toxin  nervous  symptoms  are  less  common  than  in  man. 
Edema  of  the  subcutaneous  cellular  tissue  develops  in  almost 
the  same  way  as  in  the  guinea-pig. 

We  may  thus  explain  why  an  exactly  neutral  mixture,  that 
is,  one  which  contains  no  excess  of  antitoxin  but  may  contain 
an  excess  of  toxin  which  is  not  pathogenic  for  the  guinea-pig 
will  be  also  neutral  for  the  horse,  slightly  pathogenic  for 
man,  more  so  for  the  rabbit,  and  frankly  toxic  for  birds  which 
are  the  most  sensitive  animals.  For  the  same  reasons,  fixa- 
tion of  diphtheria  toxin  by  cellular  tissue  should  be  considered 
a  reaction  of  preservation  against  reactions  more  pathogenic 
for  nervous  tissue.  The  larger  and  stronger  the  barrier 
which  holds  toxins  in  place  in  cellular  tissue,  the  less  will  be 
the  chance  for  these  toxins  to  approach  nervous  tissue. 

The  total  of  these  facts  permits  us  to  represent  the  patho- 
genicity and  evolution  of  diphtheria  in  the  following  manner. 
•Toxins  secreted  by  bacteria  are  developed  in  the  mucous 
membranes  of  the  throat,  penetrate  to  the  subjacent  cellular 
tissue  and  combine  with  the  normal  antibody  of  this  tissue. 
The  two  extreme  things  which  may  then  happen  are : 

1 .  The  quantity  or  the  virulence  of  the  toxin  secreted  may 
correspond  exactly  to  the  quantity  of  normal  antibody  which 
can  neutralize  and  digest  it  without  difficulty  and  there  will 
thus  be  local  immunity;  and  if  the  process  lasts  long  enough 
for  the  antibody  to  be  able  to  reproduce  itself  in  excess  and 
to  pass  into  the  blood  as  antitoxin  there  will  also  be  general 
immunity. 

2.  The  quantity  or  the  virulence  of  the  secreted  toxin  or 
rather  the  rapidity  of  the  secretion  may  be  too  great  for  the 
cellular  tissue  to  be  able  to  fix  and  retain  it,  so  that  a  part  of 
this  toxin  will  then  pass  into  the  organism  and  will  produce 

1  Loc.  cit. 


50       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

severe  disturbances  which,  if  there  is  no  timely  intervention, 
may  result  fatally.  Between  these  two  extremes  we  may 
imagine  an  infinite  variety  of  pathologic  manifestations  and 
local  or  general  immunizations.  As  we  have  indicated  above, 
acquired  immunity  will  always  be  inversely  proportional  to 
the  severity  of  the  attack. 

But  in  this  short  discussion  which  has  at  the  moment  no 
other  object  than  to  present  in  a  certain  order  and  to  corre- 
late a  total  of  experimental  and  clinical  facts  most  of  which 
result  from  the  memorable  researches  of  Roux  and  Yersin, 
Behring  and  Kitasato,  Vaillard,  Ehrlich,  L.  Martin,  Grancher, 
Marfan  and  others:  and  to  bring  out  the  difference  in  the 
evolution  of  diphtheria  and  most  of  the  other  infectious  dis- 
eases, we  must  dwell  upon  the  exact  significance  of  the 
"incubation  period"  in  pathologic  states  caused  by  antigens. 

We  are  accustomed  to  designate  the  time  which  intervenes 
between  contagion  and  the  appearance  of  the  first  symptoms 
or,  in  other  words  the  onset  of  disease,  as  the  "period  of 
incubation."  The  studies  of  Ch.  Richet,  Hamburger  and 
Moro,  Krauss,  Besredka  and  Mile.  Harde,  Vaughan,  Jobling 
and  others  have  shown  that  in  the  great  majority  of  infectious 
diseases  as  well  as  in  pathologic  states  caused  by  previous 
injections  of  heterologous  albumins,  of  antigens,  the  "  period 
of  disease"  coincides  almost  exactly  with  the  appearance  of 
specific  antibodies  in  excess  in  the  blood  and  we  have  been 
able  to  establish  that  the  symptomatology  of  all  these  patho- 
logic states  is  determined  by  the  nature  and  the  site  of*  the 
reaction  between  antibodies  and  antigens. 

We  may  thus  characterize  the  "period  of  incubation"  by 
reactions  of  antigens  with  normal  antibodies;  and  the  "period 
of  disease"  by  the  reaction  of  antigens  with  antibodies  in 
excess. 

But  if  we  admit  these  distinctions  and  this  seems  neces- 
sary, we  assume  that  in  diphtheria  and  in  the  diseases  analo- 
gous by  the  nature  and  action  of  their  antigens  (tetanus  and 
botulism),  the  pathological  manifestations  appear  during 
the  "period  of  incubation"  while  the  "period  of  disease"  is 
concerned  with  recovery;  all  of  which  is  contrary  to  what 
happens  in  the  great  majority  of  infectious  diseases  and  in 


TUBERCULOSIS  51 

every  case  of  anaphylaxis.  This  fact  is  explained  quite  natu- 
rally when  we  assume  that  toxins  form  with  their  antitoxins 
compounds  which  are  absolutely  neutral  for  the  organism 
and  that  antitoxins  in  excess  can  neutralize  not  only  the 
excess  of  toxins  which  has  passed  into  the  circulation  but  also 
by  virtue  of  its  mass  action  the  toxins  fixed  "en  surcharge" 
by  the  cells. 

To  summarize.  By  taking  as  a  basis,  the  nature  of  the 
infection,  the  nature  and  physicochemical  as  well  as  bio- 
logical properties  of  the  secretions  of  the  diphtheria  bacillus, 
in  other  words,  of  its  antigen  as  well  as  the  nature  and  the 
physicochemical  properties  of  the  compounds  which  this 
antigen  can  form  with  its  normal  antibody  and  with  the 
antibody  in  excess  (antitoxin),  we  may  characterize  diph- 
theria in  the  following  way : 

Diphtheria— local,  infectious  disease. 

Antigen  colloidal,  soluble,  directly  toxic.  Without  incu- 
bation. Affinity  especially  for  the  cells  of  tissues  of  ecto- 
dermic  origin. 

Normal  an/i6o<:Zi/— intracellular.  Can  fix  the  antigen  "en 
surcharge."  Compounds  of  the  antigen  with  antibodies  are 
soluble. 

Intracellular  Reactions: 

1.  Immunizing  for  the  cells  and  for  the  organism,  if  the 
quantities  of  antigen  and  antibody  are  equivalent  or  if  there 
is  an  excess  of  antibody. 

2.  More  or  less  pathogenic  if  there  is  an  excess  of  antigen 
and  fixation  of  this  latter  by  the  cellular  antibody  "en  sur- 
charge." 

Intravascular  Reactions.  — y^eutral  compounds  soluble  and 
directly  assimilable  or  eliminable  provided  the  quantities  of 
antigen  and  antibody  (antitoxin)  are  equivalent  or  if  the 
latter  are  in  excess.  Can  never  provoke  anaphylactic  hyper- 
sensitiveness. 

TUBERCULOSIS. 

A  type  of  evolution  quite  different  is  represented  by 
tuberculosis. 

Contrary  to  what  we  have  seen  for  diphtheria  toxin,  the 


52       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

tuberculous  antigen,  tuberculin,  exerts  apparently  no  direct 
pathogenic  action  on  organs  or  normal  tissues.  But  we  know 
that  a  dose  of  tuberculin  known  to  be  harmless  for  the  normal 
organism,  or  even  a  much  smaller  dose,  will  provoke  in  a  tuber- 
culous patient  a  general  reaction  more  or  less  severe  when 
injected  under  the  skin  or  into  the  blood  and  a  local  reaction 
when  a  drop  of  it  is  placed  on  a  break  in  the  skin  (cuti- 
reaction)  or  on  the  cornea  (oculoreaction).  We  also  know 
by  the  reaction  of  complement  fixation  that  this  general  and 
local  hypersensitiveness  coincides  with  the  existence  of  a 
specific  antibody  in  the  blood. 

But  this  antibody  does  not  neutralize  tuberculin  in  vitro, 
A  mixture  of  it  with  tuberculin  will  cause  a  general  and  local 
reaction  identical  to  those  provoked  by  tuberculin  alone. 
We  have  a  total  of  facts  which  seem  contradictory.  The  prob- 
lem of  the  evolution  of  tuberculosis  is  much  more  compli- 
cated than  that  of  diphtheria.  To  solve  it,  it  is  necessary 
to  analyze  carefully  each  of  the  elements  which  compose  it. 
Before  beginning  this  study  it  is  necessary  to  explain  the 
exact  meaning  of  the  terms  which  will  be  employed  in  what 
follows. 

We  will  define : 

1.  Artificial  tuberculin  as  the  total  of  the  secretions  of  the 
tubercle  bacillus  obtained  in  vitro,  whatever  may  be  the 
culture  medium  and  the  method  employed  in  its  preparation. 

2.  Natural  tuberculin,  as  the  total  of  the  products  secreted 
by  the  bacilli  in  vivo  during  infection. 

3.  Normal  antibody,  as  the  intracellular  substance  which 
possesses  a  specific  affinity  for  tuberculin  and  which  combines 
with  it  in  the  interior  of  cells;  and 

4.  Antibody  in  excess,  or  antituberculin  as  the  same  sub- 
stance as  the  normal  antibody  but  multiplied  and  existing 
in  excess  in  the  tissues  and  in  the  blood  of  the  diseased. 

After  reviewing  the  total  of  experunental  work  and  clinical 
observations  published  on  tuberculosis  and  tuberculin  since 
Koch's  discovery  of  the  germ  and  the  facts  well  established 
and  verified  by  numerous  experiments;  we  know  that  artificial 
tuberculin  does  not  act  on  normal  tissues  and  that  repeated 
injections  of  this  product  do  not  provoke  the  formation  of  an 


TUBERCULOSIS  53 

antibody  in  excess  comparable,  for  example,  to  diphtheria 
antitoxin  in  the  organism.  But  that  natural  tuberculin 
becomes  pathogenic  for  these  tissues  after  a  longer  or  shorter 
incubation  and  that  this  natural  tuberculin  provokes  in  the 
affected  organism  the  formation  of  specific  antibodies  in  excess 
which  can  be  found  in  the  blood  (reaction  of  fixation)  and  in 
the  tissues  (cutireaction) . 

From  the  fact  that  a  true  antigen  can  act  only  on  a  sus- 
ceptible organism,  one  ought  to  assume  that  artificial  and 
natural  tuberculin  are  two  different  substances  since  the 
normal  organism  seems  insensible  to  the  action  of  the  first 
and  on  the  contrary,  acquires  a  specific  sensitiveness  to  the 
action  of  the  second. 

This  suggests  that  there  is  in  the  cells  a  normal  antibody 
for  natural  tuberculin  but  no  normal  antibody  for  artificial 
tuberculin  and  from  the  point  of  view  of  specificity  of  antigens 
this  would  be  a  very  important  point  of  difference.  Moreover 
we  know  with  some  certainty  that  artificial  tuberculin  pro- 
duces on  the  tissues  of  an  organism  infected  by  tuberculosis, 
reactions  which  are  identical  to  those  which  natural  tuber- 
culin produces  in  tuberculous  foci.  There  is  then  a  contra- 
diction, but  a  close  analysis  of  the  known  facts  will  easily 
demonstrate  that  this  contradiction  is  only  apparent. 

By  studying  the  development  of  a  tuberculous  lesion,  we 
find,  according  to  the  researches  of  Besredka  and  others,  that 
lesions  around  tuberculous  foci  become  manifest  only  some 
time  after  the  appearance  in  the  blood  of  patients  of  the  anti- 
body in  excess  and  a  positive  cutireaction  shows  at  the  same 
time  that  the  tissues  of  a  tuberculous  individual  are  impreg- 
nated with  this  antibody  in  excess  at  a  time  when  not  a  single 
clinical  symptom  reveals  the  presence  of  a  tuberculous  focus. 
The  jjresence  of  antibody  in  excess  in  the  blood  is  thus  anindis- 
pensable  condition  to  pathogenic  reaction  and  if  this  is  so,  we 
may  represent  the  evolution  of  the  tuberculous  lesion  in  the 
following  manner: 

The  bacteria  of  a  tuberculous  focus  secrete  natural  tuber- 
culin of  which  a  part  is  fixed  by  the  cells  of  the  surrounding 
tissue  while  another  part,  "the  excess,"  diffuses  into  the  gen- 
eral economy.  We  will  see  later  what  happens  to  this  excess. 


54       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

For  the  moment  we  can  say  with  certainty  that  this  natural 
tuberculin  is  no  more  pathogenic  for  healthy  tissues  than 
artificial  tuberculin.  The  one  and  the  other  become  patho- 
genic only  when  in  combination  with  tuberculous  antibody 
in  the  interior  of  cells.  If  natural  tuberculin  provokes  the 
formation  of  antibodies  in  excess,  and  if  it  has  not  been  pos- 
sible up  to  the  present  time  to  obtain  an  analogous  hyper- 
sensitization  by  repeated  injections  of  artificial  tuberculin,  it 
is  very  probably  because  the  injections,  even  if  often  repeated, 
do  not  act  in  the  same  way  as  the  slow  but  steady  diffusion 
of  the  bacterial  secretion  from  a  tuberculous  focus.  We  can 
also  say  with  certainty  that  it  is  in  consequence  of  the  action 
of  these  bacterial  secretions,  harmless  for  normal  tissues,  that 
antibody  in  excess  is  formed  and  we  must  necessarily  con- 
clude that  normal  intracellular  antibody  can  fix  tuberculin 
in  quantity  strictly  immunizing  or,  in  other  words,  easily  diges- 
tible and  hence  not  pathogenic  for  the  cell.  There  is  here  no 
fixation  by  the  normal  antituberculin  of  tuberculin  "en 
surcharge,"  which  might  be  directly  toxic  as  in  the  case  of 
diphtheria  antitoxin  and  toxin.  This  immunizing  action  has 
the  effect  of  multiplying  the  normal  antibody  of  which  a 
certain  quantity  remains  in  the  sensitive  cells  and  of  which 
the  surplus  passes  into  the  circulation.  Experience  has 
shown  that  tuberculin  secreted  by  a  tuberculous  focus  pene- 
trates throughout  the  organism  and  that  it  provokes  immu- 
nizing reactions  in  every  tissue,  especially  in  those  of  ecto- 
dermal origin. 

At  a  given  moment  after  an  incubation  period,  longer  or 
shorter  according  to  the  virulence  of  the  bacteria  and  the 
number  of  foci,  all  the  sensitive  cells  of  the  organism  especially 
those  near  the  infectious  foci  are  surcharged  with  antituber- 
culin. That  phase  of  the  evolution  of  the  disease  which 
corresponds  in  diphtheria  to  immunization  and  recovery 
(because  the  combination  of  toxin  with  an  excess  of  antitoxin 
is  completely  neutral  for  the  organism)  determines  in  tuber- 
culosis the  beginning  of  the  pathologic  state  because  the 
compound  of  tuberculin  and  antituberculin  fixed  in  the  cells- 
is  pathogenic  for  the  cells. 

Thus  for  diphtheria  it  is  the  surcharge  of  toxin;  for  tuber- 


TVBEltCULOStS  55 

culosis  it  is  the  surcharge  of  antibody  in  the  interior  of  the  cells 
which  determines  the  pathologic  moment  and  the  lesion. 

It  seems  that  this  intracellular  surcharge  of  antituberculin 
is  not  indifferent  for  the  organism  even  without  the  inter- 
vention of  tuberculin.  In  fact  although  an  animal  strongly 
immunized  and  surcharged  with  diphtheria  or  tetanus  anti- 
toxin does  not  seem  to  suffer  at  all,  a  man  or  an  animal  sur- 
charged with  tuberculous  antibody  becomes  rapidly  hyper- 
sensitive to  all  sorts  of  external  agents  such  as  changes  in 
temperature,  fatigue  and  especially  a  series  of  non-specific 
products  such  as  the  antigens  of  pneumococci,  pyocyaneous, 
Metchnikoff's  vibrio,  divers  sera,  creosote,  etc.  This  non- 
specific hypersensitiveness  may  be  explained  by  the  hypo- 
thesis that  the  substance  which  constitutes  the  tuberculous 
antibody  in  the  cell  is  called  upon  to  play  a  more  important 
role  in  the  life  of  this  cell  than,  for  example,  diphtheria  anti- 
body, and  that  the  cell  cannot  easily  rid  itself  of  the  excess 
of  antibody  which  it  has  produced.  In  a  word  there  results 
a  sort  of  hypertrophy  of  an  intracellular  organ  and  of  a 
function  which  thus  becomes  abnormal  and  harmful  for  the 
cell  and  for  the  organism. 

An  interpretation  according  to  these  theories  of  some  of 
the  facts  determined  experimentally  by  A.  K.  Krause^  may 
serve  to  clarify  the  discussion: 

This  investigator  found  that  a  subcutaneous  injection  of 
living  tubercle  bacilli  into  a  normal  guinea-pig  will  cause  in 
this  animal  a  local  lesion  (reaction)  which  will  appear  only 
after  a  relatively  long  incubation  period. 

However,  a  guinea-pig  treated  in  this  way,  will,  after  the 
healing  of  this  local  lesion  or  tubercle,  always  react  to  a  new 
dose  of  tubercle  bacilli  (or  tuberculin)  in  a  very  different 
way  from  the  first  reaction. 

The  second  dose,  if  given  subcutaneously,  will  produce  a 
second  tubercle  but  in  a  very  short  time  and  the  lesion  w^ill 
be  by  comparison,  large  and  severe.  However,  instead  of 
slowly  progressing  in  size  perhaps  until  the  death  of  the 
animal,  the  initial  severity  will  soon  subside  and  the 
"tubercle"  will  heal. 

1  Kraiise,  A.  K.:  Jour.  Med.  Research,  1916. 


I 
56       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

Another  point:  Artificial  tuberculin  applied  to  the  skin  or 
the  eye  of  the  first  guinea-pig  will  not  evoke  a  reaction  until 
after  the  tubercle  has  been  established  and  has  begun  to 
heal— and  this  test  can  thereafter  be  elicited  throughout  the 
life  of  this  guinea-pig  unless  at  some  time  the  animal  is  over- 
whelmed by  a  "miliary  tuberculosis." 

In  a  normal  pig,  a  "tubercle"  does  not  appear  until  the 
production  of  antituberculin  in  excess.  This  antituberculin 
in  excess  remains  in  all  the  cells  of  the  guinea-pig  "  en  sur- 
charge" and  can  fix  to  these  cells  in  equal  quantity  its  own 
"anti"— that  is  to  say,  tuberculin  whether  artificial  or  natural 
whenever  injected.  And  in  this  way  is  explained  the  local 
and  general  reactions  of  the  second  injections.  That  this 
second  dose  produces  only  a  temporary  reaction  and  that  the 
animal  ultimately  recovers  (showing  immunity)  is  explained 
by  the  persistence  of  antituberculin. 

However,  when  the  available  antituberculin  is  less  than  the 
new  dose  of  tuberculin,  the  organism  will  be  overwhelmed, 
local  skin  and  eye  reactions  can  be  no  longer  produced  and 
the  animal  will  die. 

Let  us  now  return  to  the  tuberculous  focus.  The  bacteria 
of  this  focus  secrete  tuberculin  which  spreads  to  the  sur- 
rounding tissues  and  causes  in  the  cells  a  multiplication  of 
antibodies.  These  cells  then  become  capable  of  fixing  larger 
and  larger  quantities  of  tuberculin  without  pathologic  mani- 
festation up  to  a  certain  limit  (greater  and  greater  immunity 
to  tuberculin).  When  this  limit  is  passed  the  quantity  of 
antituberculin  en  surcharge  forms  with  tuberculin  pathogenic 
compounds  and  it  is  only  then  that  the  lesion  appears. 

The  first  phase  of  the  infection,  therefore,  corresponds 
to  the  incubation  period,  the  second  phase  to  the  period  of 
disease.  It  is  thus  evident  that  from  the  beginning  of  the 
infection,  the  evolution  of  a  tuberculous  focus  will  be  deter- 
mined by  the  three  following  factors : 

1.  The  quantity  of  tuberculin  secreted  by  the  bacteria. 

2.  The  multiplication  of  the  antibodies  in  the  cells  which 
surround  the  focus. 

3.  The  quantity  of  tuberculin  which  is  fixed  by  the  cells 
and  which  will  diffuse  into  the  general  economy. 


TUBERCULOSIS  57 

Experience  shows  clearly  that  the  production  of  antibody 
far  exceeds  the  production  of  tuberculin.  Besredka  deter- 
mined that  in  the  blood  of  guinea-pigs,  antituberculin  in 
excess  appeared  four  days  after  the  infecting  injection  and 
before  any  pathologic  manifestation,  either  local  or  general. 
In  consequence  there  is  in  the  evolution  of  a  tuberculous 
focus  a  period  during  which  all  the  tuberculin  secreted  by  the 
bacteria  will  be  fixed  in  the  focus  or  the  surrounding  tissue. 
During  this  period  the  excess  production  of  antituberculin 
will  be  forcibly  stopped,  the  quantity  of  it  which  circulates 
in  the  blood  will  progressively  diminish  and  at  the  same 
time,  thanks  to  the  intervention  of  leukocytes,  the  tuber- 
culous focus  can  be  isolated  from  the  remainder  of  the 
organism  without  forming  a  sequestrum.  The  lesion  may 
definitely  heal  by  a  mechanisin  which  we  will  examine  later 
leaving  a  scar,  or  a  focus  can  remain  in  a  latent  condition 
for  a  longer  or  shorter  time  and  can  be  revivified  by  the  onset 
of  another  disease  or  sometimes  even  by  a  simple  traumatism. 
The  excess  production  of  antibody  in  the  cells  thus  becomes 
the  cause  of  the  lesion  and  of  a  possible  cure. 

Summary. — There  results  from  the  total  of  studies  on 
the  properties  of  tuberculin  and  antituberculin  as  well  as  on 
the  reciprocal  reactions  of  these  substances  on  the  organism : 

First.— That  all  tuberculins,  regardless  of  their  method  of 
"preparation  and  origin  {in  artificial  broth  cultures  or  infectious 
foci)  J  act  by  the  same  principle  of  pathogenicity,  and  that  the 
observed  difference  of  action  results  only  from  their  concentra- 
tion and  from  the  medium  in  which  they  are  placed.  The 
biologic  differences  which  are  observed  may  be  of  the  same 
sort  as  those,  for  example,  which  are  found  in  wines  of  differ- 
ent ages  in  which  the  alcohol,  always  the  same,  but  in  greater 
or  less  quantity  may  be  associated  with  all  sorts  of  substances 
which  modify  its  action  in  a  very  definite  way.  We  may 
assume  with  the  certainty  that  the  virulence  of  all  germs 
depends  only  on  the  quantity  of  the  pathogenic  sub- 
stance secreted  which  passes  to  the  free  state  in  the  external 
medium. 

Second.—  That  antituberculin  which  multiplies  in  the  cells 
by  the  action  of  tuberculin  remains  attached  in  the  cells  probably 


58       EVOLUTION  OF  Tti^  INFECTIOUS  DISEASES 

by  bonds  which  have  vitally  important  functions  to  fulfill;  the 
cells  may  thus  be  surcharged  mth  antituberculin. 

Third.— That  the  cells  surcharged  with  antituberculin  fix 
corresponding  quantities  of  tuberculin  and  that  it  is  on  account 
of  this  abnormal  quantity  that  the  compound  of  tuberculin  and 
antituberculin  becomes  pathogenic  for  the  cells. 

Fourth.—  That  the  excess  of  antituberculin  confers  on  the 
cells  and  on  the  organism  a  nonspecific  hypersensitiveness  to 
every  sort  of  foreign  agent  as  well  as  a  specific  hypersensitiveness 
to  tuberculin. 

Fifth.—  That  granting  this  is  true,  the  impossibility  of  an 
antituberculin  immunity  such  as  one  finds  in  d  phtheria  is 
easily  explained. 

Moreover  the  studies  of  Koch,  Neufeld,  Klimmer,  Behring, 
F.  Arloing,  Chauveau,  Calmette  and  Guerin,  Vallee  and 
others,  on  vaccination  of  calves  have  shown  that  it  is  possible 
to  increase  the  resistance  of  these  animals  to  experimental 
tuberculous  infection  or  to  natural  contagions  and  although 
it  is  impossible  to  obtain  this  relative  immunity  by  bacterial 
secretions,  it  ought  to  be  obtained  by  the  intervention  of 
bacterial  bodies,  in  other  words,  by  the  reactions  of  the 
organism  against  the  germ. 

What  are  these  reactions?  The  study  of  this  question  is 
less  advanced  than  that  of  the  reactions  between  tuberculin 
and  antituberculin  although  it  has  been  established  with 
certainty. 

First,  that  the  "preparatory"  injections  of  tuberculous 
cultures,  dead  or  alive,  but  not  virulent,  provoke  in  the 
organism  the  formation  of  an  antibody  which  agglutinates 
and  precipitates  the  germs  in  vitro. 

Second,  that  the  bacteria,  dead  or  alive  and  a  virulent,  are 
more  or  less  rapidly  absorbed;  that  is  to  say,  digested  by  the 
organism. 

Third,  that  if  this  absorption  is  complete,  acquired  immun- 
ity is  of  short  duration,  less  than  one  year. 

Fourth,  that  if,  on  the  other  hand,  digest' on  of  living  germs 
injected  as  a  vaccine  is  not  complete  there  are  formed  small 
latent  infectious  foci.  Immunity  against  one  injection  or  one 
virulent  contagion  lasts  a  long  time  as  the  bacteria  in  these 
foci  live. 


I 


TUBERCULOSIS  59 

Fifth,  and  finally,  an  attack  of  tuberculosis  spontaneously 
cured  does  not  confer  a  longer  immunity  than  a  healed  vac- 
cination (Calmette,  Vallee).  Tuberculosis  thus  resembles 
syphilis  in  which  the  possibility  of  a  spontaneous  reinfection 
is  considered  as  a  proof  of  previous  cure. 

In  considering  the  total  of  reactions  provoked  in  the 
organism  by  the  secretion  of  living  tubercle  bacilli  and  by 
the  digestion  of  these  bacilli  which  goes  on  under  conditions 
which  are  as  yet  impossible  for  us  to  define  in  a  wholly  satis- 
factory way,  we  can  represent  the  evolution  of  spontaneous 
tuberculous  infection  in  the  following  manner: 

The  bacteria  which  penetrate  into  the  organism  by  the 
digestive  of  respiratory  tracts  are  taken  into  the  circulation 
and  may  remain  there  for  a  longer  or  shorter  time  before 
being  fixed  in  the  different  tissues,  glands  and  organs.  A 
certain  proportion  of  these  fixed  bacteria,  all  the  greater 
when  the  bacteria  are  less  virulent  (when  they  secrete  less 
pure  tuberculin),  and  mce  versa  are  certainly  digested  and 
produce  a  precipitating  antibody  which  w^e  may  call  anti- 
bacillin.  This  function  belongs  properly  to  the  bacteria 
fixed  in  the  organs.  Those  which  are  fixed  in  the  tissues 
secrete  tuberculin  and  become  the  origin  of  infectious  foci 
and  of  lesions,  whose  evolution  has  been  analyzed  above. 
The  successive  phases  of  the  disease  are  thus  determined 
first  by  the  digestion  of  bacteria  and  the  production  of  anti- 
bacillin,  and  second  by  the  secretion  of  tuberculin  and  the 
production  of  antituberculin. 

If  the  bacteria  are  less  virulent  the  proportion  of  those 
which  are  digested  and  which  produce  antibacillin  is  greater 
than  the  proportion  of  those  which  are  fixed  in  the  tissues  and 
which  produce  the  formation  of  antituberculin  in  excess. 
On  the  contrary,  when  the  bacteria  are  virulent  it  is  the  anti- 
tuberculin reaction  which  predominates;  infectious  foci  be- 
come more  numerous  and  lesions  more  severe. 

The  experiments  of  Besredka,  and  of  Manoukhine  show 
with  sufficient  precision  the  evolution  of  the  antituberculin 
reactions  in  the  successive  phases  of  tuberculosis  in  the 
guinea-pig.  In  these  very  sensitive  animals  antituberculin 
appears  in  the  blood  four  days  after  the  injection  of  the  virus; 


60       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

its  quantity  increases  up  to  the  fiftieth  or  eightieth  day,  falls 
and  increases  again  at  about  the  ninetieth  day  and  disappears 
completely  some  few  days  before  death.  Thus  the  disease 
develops  parallel  to  the  production  of  antituberculin.  The 
temporary  disappearances  of  antituberculin  from  the  blood 
are  the  consequence  of  the  limitation  of  the  bacterial  secre- 
tions to  the  tissues  which  surround  the  infectious  foci  because 
of  antituberculin  in  excess  and  as  soon  as  this  excess  dis- 
appears from  the  circulation  the  same  process  begins  again 
if  not  finally  stopped  by  the  death  of  the  animal.  The 
extreme  susceptibility  of  the  guinea-pig  for  tuberculosis 
probably  arises  from  the  almost  absolute  incapacity  of  this 
animal  to  digest  Koch's  bacillus  and  to  produce  antituber- 
culin. 

Such  are  the  general  principles  which  determine  the  evolu- 
tion of  pathogenicity  of  tuberculosis  in  so  far  as  experiments 
and  clinical  observations  permit  us  to  formulate  them.  They 
may  be  summarized  in  a  few  lines : 

1.  Infection  is  followed  by  an  incubation  period  during 
which  the  digestive  attack  of  the  bacterial  secretions  and  of 
the  bacteria  themselves  results  in  the  production  of  anti- 
tuberculin and  antibacillin. 

2.  The  period  of  disease  begins  at  the  moment  when 
intracellular  antituberculin  in  excess  has  fixed  a  sufficient 
quantity  of  tuberculin  so  that  the  compound  of  tuberculin 
with  antituberculin  which  is  fixed  in  the  cell  can  become 
pathogenic  (undigestible)  for  the  cells  themselves. 

3.  Antibacillin  aids  in  the  destruction  of  the  bacteria 
which  are  multiplied  in  the  organism. 

4.  The  different  phases  of  the  evolution  of  the  disease  are 
determined  on  the  one  hand  by  the  number  and  the  stage  of 
development  of  the  tuberculous  foci  (that  is  to  say  by  reac- 
tions successively  immunizing  and  pathogenic  between 
tuberculin  and  antituberculin):  on  the  other  hand  by  the 
reactions  of  the  antituberculin  with  the  bacteria.  During 
this  disease  period  pathologic  impulses  which  follow  one 
another  at  longer  or  shorter  intervals  and  characterized  by 
fever,  lassitude,  sweats,  etc.,  are  provoked  by  the  local  or 
general  rupture  of  the  antituberculin  blockade.     In  case 


TUBERCULOSIS  61 

of  local  rupture  the  tuberculin  thus  liberated  provokes  a  con- 
gestive reaction  in  all  the  other  foci;  quite  as  an  artificial 
injection  of  tuberculin. 

5.  Each  of  these  impulses  may  be  followed  by  a  definite 
recovery,  thanks  to  the  intervention  of  antibacillin  or  by  an 
aggravation  of  the  disease  caused  by  the  bacteria  thus 
liberated  and  not  destroyed,  which  become  centers  for  new 
foci  and  new  lesions. 

6.  Immunity  acquired  by  the  healing  of  a  spontaneous 
or  artificia'  infection  is  of  short  duration,  most  probably 
because  the  production  of  antibacillin  is  rapidly  stopped  after 
the  disappearance  of  bacteria. 

7.  We  may  consider  it  as  proved  that  the  presence  of  living 
avirulent  bacteria  in  the  organism  confers  on  cattle  a  com- 
plete immunity  against  virulent  reinfections. 

Tuberculosis  may  be  characterized  in  the  following 
manner : 

Disease  of  local  infectious  foci  which  may  give  rise  to  septi- 
cemic metastases. 

Antigen  soluble  (tuberculin),  non-pathogenic  for  normal 
tissues  as  it  cannot  be  fixed  by  antibodies  en  surcharge. 

Normal  antibody  intracellular  can  multiply  in  the  cells  in 
excess  and  remain  fixed  in  the  interior  of  cells  "en  surcharge." 

Intracellular  antibody  "en  surcharge"  (antituberculin)  is 
pathogenic  for    the   cells— hypersensitiveness    non-specific. 

Intracellular  compound  of  normal  antibody  and  antigen  is 
non-pathogenic  (digestible)  and  causes  the  multiplication  of 
antibodies. 

Intracellular  compound  of  antibody  en  surcharge  and  of 
antigen  is  pathogenic  (non-digestible)  for  the  cells  and  causes 
the  destruction  of  the  cells. 

Bacterial  antigen  (bacterial  bodies  cause  the  formation  of 
a  specific  agglutinating  antibody  (antibacillin) . 

Antibacillary  immunity  not  antitoxic  immunity. 

Intracelhdar  anaphylaxis  and  not  intravascular  anaphylaxis. 

From  the  total  of  the  theories  which  we  have  just  reviewed 
we  are  forced  to  conclude  that  in  tuberculosis  it  may  not  only 


62       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

be  a  question  of  an  immunity  from  antituberculin  but  since 
it  is  shown  that  tuberculosis  can  heal  spontaneously  and 
that  a  certain  relative  immunity  may  be  obtained  by  bac- 
terial vaccination  we  should  necessarily  assume  that  a 
bacterial  therapy  and  a  specific  chemotherapy  should  very 
appreciably  aid  the  destruction  of  the  bacteria.  Serum 
therapy  would  be  applicable  only  in  the  stages  of  the  disease 
during  which  one  could  establish  the  absence  in  the  organism 
of  antibody  in  excess. 

TYPHOID  FEVER. 

We  know  that  completely  digested  albumins,  that  is  to 
say,  those  which  are  transformed  to  their  amino-acids  are 
not  antigens,  while  albumins  themselves  as  well  as  all  incom- 
pletely digested  compound  are  antigens.  We  must  suppose 
that  in  infections  of  intestinal  origin  bacteria  as  well  as  the 
products  of  bacteria  can  resist  digestion  and  can  penetrate 
into  the  cells  and  capillaries  of  the  intestinal  mucosa  and 
that  only  the  individual  and  the  species  unable  to  digest  the 
bacteria  and  reduce  them  to  amino-acids  can  be  infected  in 
this  way.  It  is  at  present  not  possible  to  follow  all  the  phases 
of  the  pathogenicity  of  typhoid  fever  in  man,  but  it  can  be 
done  in  paratyphoid  fever  of  young  rodents  and  the  patho- 
genicity can  be  represented  as  follows : 

Bacteria  enter  by  the  mouth,  are  in  large  part  destroyed 
in  the  stomach  but  the  products  of  this  destruction  are  not 
completely  digested  and  pass  with  the  surviving  bacteria 
into  the  intestines  where  these  latter  can  multiply  until  the 
bacterial  products  which  resist  intestinal  digestion  are  in 
part  absorbed  by  the  cells  of  the  mucosa. 

This  primary  absorption  determines  the  formation  of 
more  or  less  severe  areas  of  congestion  analogous  to  those 
which  are  observed  when  a  small  quantity  of  dead  bacteria 
are  introduced  under  the  skin.  This  congestion  favors  in 
its  turn  the  penetration  into  the  mucosa  and  into  the  capil- 
laries of  fresh  quantities  of  bacterial  products  and  even  of 
living  bacteria.  The  result  is  that  the  severity  of  the  con- 
gestion is  increased. 


TYPHOID  FEVER  63 

The  first  bacteria  which  penetrate  into  the  blood  are 
engulfed  by  leukocytes  and  taken  to  the  hemopoetic  organs 
where  they  are  more  or  less  completely  destroyed  and  where 
those  which  remain  viable  produce  little  foci  of  infection 
and  lesions.  During  all  this  period  typhoid  antigens,  bac- 
terial secretions  as  well  as  products  of  bacteriolysis  are  found 
in  excess  of  the  normal  a7itibodies  which  preexist  in  the  cells 
of  every  organism  susceptible  to  the  action  of  antigens.  The 
areas  of  congestion  are  caused  by  the  fixation  "en  surcharge" 
of  antigens  by  normal  antibodies.  Thus,  for  example,  when 
an  injection  of  antigen  is  made  into  or  under  the  skin,  a  mild 
local  congestion  is  produced;  but  when  it  is  given  into  a  vein, 
there  will  be  no  appreciable  reaction  because  here  the  antigen 
will  be  distributed  to  a  much  larger  number  of  cells  and  will 
therefore  never  be  in  excess. 

Under  the  continued  action  of  new  quantities  of  antigen 
which  increase  steadily  until  the  spontaneous  death  or  destruc- 
tion of  the  bacteria,  there  are  formed  in  the  organism  larger 
and  larger  quantities  of  antibodies.  The  excess  of  these  is  at 
first  stored  "en  surcharge"  in  the  cells  in  which  it  is  formed; 
but  after  a  certain  maximum  is  reached,  this  excess  is  finally 
thrown  off  into  the  blood  by  a  series  of  sudden  discharges. 

At  a  certain  given  moment  the  antibody  thus  appears  in 
excess  in  the  blood  in  spite  of  the  continued  multiplication 
of  bacteria  and  we  must  necessarily  conclude  that  the  pro- 
duction of  antibody  is  more  rapid  than  that  of  antigen.  The 
moment  at  which  we  begin  to  find  antibody  in  excess  in  the 
blood  coincides  generally  with  the  appearance  of  the  first 
severe  symptoms  which  characterize  the  disease.  This  is 
the  end  of  the  period  of  incubation  and  the  beginning  of  the 
period  of  disease. 

If  then  one  could  describe  the  condition  in  which  the 
infected  organism  is  found  from  the  point  of  view  of  immunity 
and  anaphylaxis  or  if  we  could  stop  the  evolution  of  the 
infection  at  the  end  of  the  incubation  period  or  at  the  moment 
of  the  appearance  of  antibodies  in  excess  we  would  find  that 
the  organism  had  developed  a  greater  resistance  to  a  new 
infection,  in  other  words,  that  it  had  acquired  a  certain 
degree  of  active  anti-infectious  immunity,  and  also  that  it 
had  become  susceptible  to  active  anaphylaxis. 


64       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

The  theories  of  this  condition  cannot  be  demonstrated  by 
experiment  but  the  result  would  be  the  same  if  in  place  of  an 
infection  by  living  bacteria  the  organism  had  received  an 
injection  or  a  series  of  injections  of  dead  bacteria.  At  the 
moment  of  the  appearance  of  antibodies  in  excess  it  would 
be  immunized  against  the  dose  of  living  bacteria  pathogenic 
for  controls  and  would  be  hypersusceptible  (anaphylactic) 
to  a  non-pathogenic  dose  of  dead  bacteria  and  finally  hyper- 
susceptible to  a  dose  of  living  bacteria  greater  than  its  degree 
of  anti-infectious  immunity. 

Whether  the  bacteria  be  living  or  dead  at  the  end  of  the 
incubation  period,  the  organism  will  be  exactly  in  the  same 
condition  from  the  point  of  view  of  immunity  and  anaphylaxis. 
If  the  results  are  different  it  is  because  living  bacteria  con- 
tinue to  multiply,  but  if  the  injections  of  dead  bacteria  in 
considerable  doses  were  continued  after  the  time  when  the 
organism  became  surcharged  by  an  excess  of  antibodies  the 
picture  of  spontaneous  infectious  disease  would  be  very 
probably  and  almost  certainly  duplicated.  In  fact  practical 
antityphoid  vaccination  has  shown  that  the  subjects  more  or 
less  immunized  by  a  previous  healed  typhoid  infection  are 
infinitely  more  sensitive  to  the  vaccine  than  normal  subjects 
and  in  the  cases  of  alimentary  poisoning  caused  by  para- 
typhoid swallowed  in  modified  doses  the  crises  are  all  the 
more  severe  if  the  subjects  are  already  strongly  immunized.^ 

But  then  one  may  ask  why  does  a  spontaneous  infection 
not  stop  at  the  end  of  the  incubation  period  since  the  patient 
is  at  this  moment  more  immunized  than  at  the  start  of  the 
infection?  This  very  thing  happens  much  more  often  than 
has  been  supposed  at  the  present  time  not  only  in  typhoid 
but  in  every  other  infectious  disease.  In  certain  cases  the 
few  mild  symptoms  permit  the  recognition  of  a  disease  which 
aborts,  but  the  great  majority  of  these  cases  escape  observa- 
tion and  acquired  immunity  can  be  revealed  only  by  a  study 
of  the  serum,  by  vaccine  reaction  or  by  the  opsonic  index. 

^  A  dozen  persons,  at  least  one  of  whom  was  immunized  normally  against 
paratyphoid,  swallowed  by  accident  a  heavy  dose  of  paratyphoid  bacilli 
in  milk.  All  of  them  were  more  or  less  indisposed,  but  only  the  immu- 
nized individual  was  severely  ill. 


TYPHOID  FEVER  65 

The  explanation  of  these  facts  appears  very  simple.  The 
continued  development  of  the  disease  after  the  end  of  the 
incubation  period  or  the  abortment  necessarily  depends  upon 
the  degree  of  acquired  immunity  or  on  the  quantity  of  formed 
antibody  and  on  the  quantity  of  bacteria  which  exist  at  this 
moment  in  the  organism  because  immunity  is  only  relative 
and  the  protection  is  only  against  a  certain  minimum  dose 
of  bacteria.  Thus  the  relation  between  these  two  quantities 
which  tip  the  balance  to  one  side  or  the  other,  individual 
differences  between  the  degrees  of  natural  or  acquired  immun- 
ity at  the  moment  of  infection  and  finally  differences  of 
quantity  or  virulence  of  the  infecting  bacteria  may  be  very 
variable. 

In  the  explanation  of  the  results  of  these  reactions  it  is 
necessary  to  note:  on  the  one  hand,  the  fact,  proved  by 
experiment,  that  the  quantity  of  antibody  formed  at  a  given 
moment  as  well  as  the  rapidity  with  which  it  is  formed  is, 
within  certain  limits,  inversely  proportional  to  the  quantity 
or  the  virulence  of  the  injecting  antigen;  and,  on  the  other 
hand  that  the  final  result  of  all  these  reactions  may  depend 
not  only  upon  the  direct  action  of  the  antigen  upon  the  anti- 
body or  the  cell  which  contains  it  but  on  the  disturbance 
which  the  lesion  or  the  "complication"  once  produced  will 
cause  in  the  function  of  the  organism.  If  this  is  true,  how 
can  we  represent  the  causes  and  the  origin  of  each  pathologic 
manifestation  which  characterizes  the  septicemic  infectious 
diseases,  typhoid  fever  in  particular? 

We  know  that,  for  the  diseases  caused  by  toxins  (diph- 
theria), cure  begins  with  the  appearance  of  antibodies  in 
excess  while  in  the  case  of  typhoid  it  is  the  disease  which 
begins  precisely  at  this  moment.  We  then  afRrm  that  the 
incubation  period  of  typhoid  coincides  with  the  disease  period 
of  diphtheria  or,  to  be  more  exact,  that  in  diphtheria  there  is 
simultaneously  incubation,  from  the  point  of  view  of  produc- 
tion of  antibodies,  and  disease  with  its  pathologic  manifes- 
tations. And  if  this  is  true,  we  may  assume  by  correlating 
what  precedes  that  in  diphtheria  pathologic  manifestations 
result  from  the  direct  action  of  the  antigen-toxin  on  the 
normal  intracellular  antibody  and  that  the  compounds  of 
5 


66       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

this  antigen  with  antibody  in  excess  do  not  produce  an  active 
anaphylactic  state.  In  typhoid,  however,  we  may  suppose 
that  the  bacterial  antigen  secretion  is  not  pathogenic  for 
nonnal  tissue  or  else  that  this  secretion  is  not  the  whole 
antigen  and  that  the  pathologic  symptoms  which  are  mani- 
fested at  the  moment  of  appearance  of  antibodies  in  excess 
can  be  only  the  result  of  the  combination  of  these  antibodies 
with  antigens  produced  by  bacteriolysis.  Thus  the  syndrome 
of  the  period  of  disease  in  typhoid  in  exclusively  anaphylactic. 
From  the  point  of  view  of  pathogenicity  we  may  thus  review 
the  two  cases  by  the  following  formulae : 

Diphtheria:     Toxin   +  Normal  antibody    =   Disease. 
Toxin   +  Antibody  in  excess    =  Immunity  and  cure 
Typhoid:     Toxin  (?)    +  Normal  antibody    =   O  ? 
Products  of  bacteriolysis   +  Normal  antibody    =  Incubation. 
Products  of  bacteriolysis   +  Antibody  in  excess  =  Immunity  and 
anaphylaxis. 


Thus  we  have  seen  that  in  typhoid  there  is  no  toxin- 
secretion  nor  bacterial-antigen  analogous  to  that  of  diph- 
theria or  if  there  is  one,  it  is  neutralized  at  the  end  of  the 
incubation  period  by  the  appearance  of  antibody  in  excess 
(as  in  diphtheria)  and  can  no  longer  produce  any  apparent 
disturbance.  If  at  this  moment  it  becomes  pathogenic  it 
will  produce  only  anaphylactic  disturbances.  But  in  typhoid 
there  is  certainly  penetration  and  multiplication  of  bacteria, 
or  at  least  of  products  of  bacteriolysis  in  the  form  of  albumin 
and  it  is  absolutely  certain  that  there  are  albumins  which 
cause  disturbances  characteristic  of  the  period  of  disease  as 
in  the  case  of  every  other  heterologous  albumin  when  com- 
bined with  its  antibodies  in  excess. 

Thus  we  may  conclude  with  certainty  that  in  typhoid  the 
disease  consists  of  an  anaphylactic  crisis  which  is  chronic  or, 
in  other  words,  of  a  succession  of  anaphylactic  crises  which 
are  determined  at  each  moment  by  the  three  following  factors: 

1.  The  appearance  of  the  albumin  antigen  as  a  result  of 
the'multiplication  of  bacteria. 

Il  2.  The  quantity  of  antibodies  in  excess  formed  by  the 
organism. 


TYPHOID  FEVER  67 

3.  The  influence  of  the  lesions  in  the  different  tissues  and 
organs  on  the  general  state  of  the  organism. 

Most  if  not  all  septicemic  infectious  diseases  belong  neces- 
sarily in  the  same  class.  A  septicemic  bacteria  can  be  patho- 
genic only  in  case  its  albumin  is  antigenic  for  the  organism; 
in  which  case  there  will  always  be  anaphylaxis. 

It  is  possible  that  in  certain  cases  the  action  of  albumins 
may  be  completed  by  that  of  toxic  secretions  but  the  study  of 
these  secretions  in  the  pure  state,  that  is  to  say,  completely 
separated  from  the  products  of  bacteriolysis  is  still  too  incom- 
plete to  enable  us  to  know  whether  or  not  they  may  be  toxic 
and  may  produce  antibodies.  At  all  events,  and  we  cannot 
repeat  it  too  often,  this  question  can  have  only  a  secondary 
importance  in  the  pathogenicity  of  disturbances  observed 
during  the  disease  period  because  as  these  appear  simul- 
taneously with  the  appearance  of  antibodies  in  excess,  they 
must  be  of  an  anaphylactic  nature.  And  it  is  of  little  impor- 
tance whether  these  products  originate  exclusively  from 
albumins  or  from  exotoxins. 

St)ontaneous  Cure.— Immunity  and  anaphylaxis  are  phe- 
nomena of  a  general  nature  which  may  be  applied  to  all  living 
beings,  vegetable  or  animal,  uni-  or  pluricellular;  to  bacteria 
as  well  as  to  man.  A  bacterium  which  has  penetrated  into  the 
interior  of  a  higher  organism  must  adapt  itself  to  this  interior. 
The  organism  will  produce  an  intracellular  antibody  and  will 
be  surcharged  with  it  and  this  surcharge  will  increase  the 
degree  of  its  immunity  but  at  the  same  time  it  will  also 
increase  the  degree  of  its  anaphylaxis.  The  antibody  of  the 
infected  organism  will  become  antigenic  for  the  bacteria  in 
exactly  the  same  way  and  will  produce  on  the  bacteria  the 
same  effects  as  the  bacterial  antibody  produces  on  the 
organism. 

It  is  this  balance  between  the  degrees  of  immunity  and 
anaphylaxis  of  the  infecting  bacteria  on  the  one  hand  and 
the  infected  organism  on  the  other,  that  determines  the  issue 
in  the  struggle  between  the  two  opponents.  A  bacterium 
surcharged  with  its  antibody,  will  fix  a  quantity  of  antibody 
of  the  organism  (which  is  antigenic  for  itself)  all  the  greater 
if  its  degree  of  immunity-anaphylaxis  is  higher.    It  will  be 


68       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

"sensitized"  and  when  this  surcharge  exceeds  certain  limits 
it  will  burst  by  autolysis  or  will  become  the  easy  prey  of 
leukocytes  according  to  the  phenomenon  of  positive  chemo- 
taxis  (Ch.  Bordet  and  Massart).  In  this  way,  the  source  of 
the  infecting  antigen  will  be  exhausted.  How  can  we  inter- 
vene successfully  in  order  to  throw  the  balance  toward  the 
recovery  of  the  organism? 

Therapy. — To  judge  by  the  results  of  experiments  and 
clinical  observations  we  are  obliged  to  assume  that  the  pres- 
ence of  a  great  excess  of  antibodies  on  the  exterior  of  a  cell 
hinders  hydrolysis  of  the  antigen  fixed  to  the  interior  of  this 
cell;  in  other  words,  if  an  infecting  bacteria  has  produced  an 
excess  of  its  intracellular  antibody  (which  is  antigenic  for  the 
organism)  and  if  it  has  fixed  to  this  antibody  a  corresponding 
quantity  of  antigen  (which  is  the  antibody  produced  by  the 
organism)  it  will  not  suffer  until  there  is  antigen  in  excess  on 
its  exterior  (antibody  of  the  organism  in  the  plasma).  Bac- 
tericidal anaphylactic  shock  is  produced  only  when  there  is 
an  excess  of  antibody  in  the  exterior. 

Numerous  studies  have  shown  that  when  one  injects  a 
typhoid  patient  with  a  certain  quantity  of  dead  bacteria  the 
content  of  antigen  is  increased  and,  by  the  same  amount, 
the  quantity  of  antibody  contained  in  the  blood  is  diminished. 
At  the  same  time  a  diminution  or  even  a  complete  disappear- 
ance of  bacteria  and  a  rapid  amelioration  of  all  pathologic 
manifestations  is  found.  This  result  is  obtained  very  often, 
but  there  are  also  failures,  relapses  and  sometimes  complica- 
tions and  this  is  not  surprising  because  to  obtain  a  result 
which  is  constant  and  proved  beforehand  it  would  be  neces- 
sary to  know  the  exact  quantity  of  antigen  to  inject  in  each 
special  case  in  order  to  produce  an  anaphylactic  crisis  fatal 
to  the  bacteria.  Thus  the  antibody  of  the  organism  may  act 
on  the  bacteria  as  an  anaphylactic  or  anaphylatoxic  antigen 
and  in  order  to  provoke  an  anaphylactic  crisis  fatal  for  the 
bacteria,  certain  optima  proportions  between  the  quantity 
of  antibody  and  fixed  antigen  held  by  the  bacteria  and  the 
excess  of  this  antigen  in  the  plasma,  its  external  medium, 
are  necessary.  But  these  optima  proportions  may  vary 
widely  in  different  cases  and  as  there  is  no  theory  to  explain 


TYPHOID  FEVER  69 

the  therapeutic  action  of  antigens,  we  can  estabHsh  only  an 
empirical  means  which  may  not  always  be  the  best. 

In  laboratories  it  would  not  be  difficult  to  estimate  the 
excess  of  antibody  in  the  blood  of  the  organism,  as  well  as 
the  degree  of  immunity  anaphylaxis  of  the  bacteria  and  by 
always  using  the  same  antigen  in  exact  titer  one  would  obtain 
essentially  comparable  results.  In  the  practical  medical 
clinic  all  complications  would  very  probably  be  avoided  by 
injecting  the  antigen  in  progressively  increasing  doses  at 
intervals  of  some  minutes.  The  injections  of  dead  bacteria 
ought  to  be  given  intravenously  and  if  the  total  dose  was, 
for  example,  500  millions,  one  might  begin  by  injecting  1,  or 
2,  then  in  ten  minutes  10  and  finally  40  and  450  millions  at 
intervals  of  five  minutes.  Two  successive  injections,  1  of  5, 
the  other  of  500  millions  at  ten-minute  intervals  might  be 
perhaps  sufficient.  If  the  principle  of  skepto-  or  tachy- 
phylaxis is  good,  the  technic  would  be  easy  to  work  out. 

Preventive  Vaccination.— The  effects  of  preventive  vac- 
cination on  the  morbidity  of  typhoid  are  today  indisputable; 
what  is  not  indisputable  is  the  method  of  preparation  of 
vaccine  and  the  technic  of  vaccination.  The  heated  bac- 
terial bodies  of  Chantemesse  and  Widal;  the  more  or  less 
autolized  bacteria  of  Vincent;  the  lipovaccines  of  LeMoignic 
and  Pinoy  may  confer  the  same  degree  of  immunity  on  the 
organism  but  never  lasting  very  long. 

It  would  be  perhaps  more  interesting  to  try  to  make  the 
human  organism  refractory  to  typhoid  fever  as  all  other 
mammals  are  refractory  to  typhoid  and  for  that  it  would 
suffice  to  teach  it  to  completely  digest  typhoid  and  para- 
typhoid bacteria  as  it,  for  example,  digests  plague  bacilli. 
Bacteriotherapy  by  mouth  practiced  successfully  by  Dr. 
L.  Fournier  at  the  Cochin  Hospital  for  more  than  three  years, 
proves  indisputably  that  the  products  of  bacteriolysis  of 
Eberth's  bacillus  are  absorbed  by  the  intestinal  mucosa  as 
antigens  and  it  is  very  possible  to  assume  that  one  would  be 
able  to  stimulate  complete  gastro-intestinal  digestion  of 
bacteria  by  a  suitable  means  by  causing  children  to  ingest 
more  or  less  autolyzed  bacterial  bodies  in  progressively 
increasing  doses.     By  proceeding  in  this  way,  one  would 


70      EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

perhaps  anticipate  a  two-fold  result,  a  certain  degree  of 
immunity  for  an  infection  by  inoculation  and  a  refractory 
state  for  an  infection  by  ingestion. 

PARATYPHOID  FEVERS. 

The  evolution  of  these  diseases  is  as  a  rule  very  analogous 
to  that  of  typhoid  fever.  So  that  it  is  sufficient  to  repeat  in  a 
few  words  the  differences  sometimes  observed  in  those  dis- 
eases caused  by  paratyphoid  which  are  commonly  called 
"ptomaine  poisoning."  In  these  cases  the  ingestion  of 
infected  food  is  followed  very  rapidly  in  a  few  hours  by  a 
violent  crisis  which  simulates  an  acute  attack  of  cholera. 
When  all  the  elements  are  analyzed  it  is  found  that  the 
evolution  of  these  crises  is  only  a  repetition  of  the  typical 
evolution  of  a  normal  typhoid  infection.  There  is  no  incu- 
bation period;  the  disease  begins  full  blown.  The  differences 
in  the  progress  of  the  evolution  of  infection  will  be  determined 
in  the  two  cases : 

1.  By  the  difference  of  the  ingested  infecting  dose. 

2.  By  the  degree  of  the  permeability  of  the  intestinal 
mucosa  at  the  moment  of  infection,  and 

3.  Especially  by  the  preexistence  of  a  certain  quantity 
of  antibodies  in  the  blood. 

Bacteria  ingested  in  massive  doses  are  in  part  destroyed 
and  in  part  digested.  The  colloidal  products  of  this  digestion 
pass  rapidly  into  the  intestinal  mucosa  and  into  the  blood 
causing  congestion  and  facilitating  the  passage  of  living 
bacteria.  Bacteria  in  the  blood  are  rapidly  "sensitized"  by 
antibodies  in  excess  and  autolized  and  the  crisis  may  be 
terminated  by  death  or  recovery  in  a  few  hours  or  few  days 
at  most.  Repeated  intravenous  injection  of  specific  antigens 
or  heterologous  antigens  should  be  the  most  appropriate 
treatment  in  these  cases. 

CHOLERA. 

The  same  point  of  view  of  the  pathogenicity  of  the  evolu- 
tion of  intestinal  infectious  infections  which  we  have  just 


CHOLERA  71 

discussed  in  typhoid  is  equally  applicable  to  cholera.  The 
cholera  vibrio  is  very  proteolytic.  It  will  destroy  itself  in 
its  own  culture.  It  is  unable  to  penetrate  alive  into  the 
blood  and  the  products  of  its  bacteriolysis  find  in  the  blood 
precipitating  antibodies  already  preformed  in  combination 
with  which  they  produce  all  the  known  disturbances.  They 
act  like  the  arsenobenzenes  which  have  been  insufficiently 
alkalhiized.  In  the  case  of  fulminating  cholera,  the  crisis  is 
caused  by  the  rapid  passage  into  the  blood  of  a  great  quan- 
tity of  products  of  bacteriolysis  and  in  fact  here  we  find  none 
or  very  few  living  bacteria  in  the  intestines  (at  autopsy) . 

It  is  impossible  to  know  today  whether  the  subjects  over- 
whelmed in  this  way  have  been  more  or  less  immunized  by 
spontaneous  immunizing  infections  but  it  is  very  probable 
that  if  they  had  been  immunized,  we  should  find  that  the 
reaction  would  be  here  exclusively  intravascular. 

When  the  crisis  lasts  for  several  hours  it  begins  with 
intravascular  reactions  which  cause  disturbances  of  the 
circulation:  embolism,  dilatation  of  capillaries,  congestion 
of  mucous  membranes  and,  in  consequence,  gastro-intestinal 
disturbances  and  fall  in  temperature:  sometimes  dyspnea, 
convulsions,  and  syncope  which  may  result  fatally.  When 
the  crisis  is  prolonged,  there  are  very  probably  intracellular 
reactions  which  are  expressed  by  fever  and  may  in  turn  lead 
to  death.  But  in  the  latter  case,  the  pathologic  state  may 
result,  not  from  the  direct  action  of  the  cholera  antigen  but 
from  lesions  more  or  less  severe  and  numerous  or  from  com- 
plications produced  by  the  reactions. 

To  sum  up:  the  total  of  our  knowledge  concerning  the 
pathogenicity  and  evolution  of  gastro-intestinal  infections 
produced  by  the  bacteria  of  the  typhoid-colon  and  cholera 
group  permits  us  to  conclude: 

1.  Only  the  animal  species  or  individuals  which  are  incap- 
able of  completely  digesting,  that  is  to  say,  of  transforming 
into  non-specific  amino-acids  the  albumins  of  certain  bac- 
teria can  be  spontaneously  infected  by  those  bacteria. 

2.  The  severity  of  the  disease  is  determined  on  the  one 
hand  by  the  dose  of  bacteria  injected  as  well  as  by  the  inten- 
sity and  rapidity  of  bacteriolysis;  on  the  other  hand,  by  the 


72       EVOLUTION  OF  THE  INFECTIOUS  DISEASES 

quantity  of  normal,  antibodies  or  those  which  preexist  in 
excess;  in  other  words,  by  the  degree  of  immunity,  natural 
or  acquired. 

3.  By  taking  into  consideration: 

(a)  The  frequency  of  these  different  bacteria  in  nature 
and  consequently  the  frequency  of  infections  and  of  possible 
spontaneous  vaccinations : 

(b)  The  gastro-intestinal  digestibility  of  bacterial  bodies 
and  of  the  products  of  their  cleavage. 

(c)  The  permeability  of  the  intestinal  mucosa  for  these 
products. 

(d)  Finally  the  digestibility  of  these  products  which  have 
passed  as  antigens  into  the  interior  of  the  organism ;  we  may 
classify  these  organisms  in  the  following  way: 

1.  The  bacilli  of  Eberth  are  the  least  frequent,  giving  the 
poorest  growths  in  all  the  known  culture  media.  The  prod- 
ucts of  their  proteolysis  are  most  difficult  to  digest  in  the 
digestive  apparatus  of  man.  The  products  of  bacteriolysis 
always  begin  by  penetrating  in  small  quantity  (immunizing 
quantity)  into  the  blood  where  they  stay  during  a  relatively 
long  incubation  period.  The  compounds  of  the  antigen 
which  have  penetrated  into  the  blood  with  their  antibodies 
are  digestible  with  difficulty  in  the  interior  of  the  organism; 
on  account  of  which  lesions  are  severe  and  the  period  of 
disease  is  relatively  long. 

2.  Paratyphoid  bacilli  are  more  frequent,  giving  more 
rapidly  most  potent  cultures,  are  perhaps  more  proteolytic 
and  more  difficult  of  digestion  for  certain  animals  (hog 
cholera,  typhoid  of  mice,  psittacosis)  and  spontaneous 
vaccination  is  more  frequent.  The  products  of  bacteriolysis 
may  penetrate  from  the  intestines  into  the  blood  in  massive 
doses  and  cause  rapid  crises  of  considerable  violence  but  of 
short  duration,  since  the  subject  contains  a  larger  quantity 
of  antibody  in  his  blood  and  in  his  tissues,  or,  in  other  words, 
is  more  strongly  immunized.  The  compounds  of  antigen  with 
antibody  are  more  easily  digested  and  in  consequence  less 
pathogenic  than  those  of  typhoid. 

3.  Colon  bacilli  are  the  most  widely  distributed  of  this 
group  of  organisms  and  the  easiest  to  cultivate.    The  prod- 


CHOLERA  73 

nets  of  their  bacteriolysis  are  very  probably  completely 
digested  in  the  digestive  apparatus  and  do  not  penetrate 
into  the  blood  as  antigens  and  are  only  very  exceptionally 
pathogenic  when  taken  by  mouth. 

4.  Cholera  vibrio  are  very  widespread  in  nature,  and  very 
often  provoke  apparently  spontaneous  vaccinations,  they  are 
very  proteolytic  and  the  products  of  bacteriolysis  are  not 
completely  digested  in  the  human  gastro-intestinal  tract. 
These  products  penetrate  into  the  blood  as  antigens  and 
provoke  (as  in  the  alimentary  intoxications  caused  by  para- 
typhoid) various  circulatory  disturbances  more  or  less  severe 
according  to  the  quantity  of  antigen  absorbed  and  the 
quantity  of  preexisting  antibody.  The  living  germ  does 
not  penetrate  into  the  blood. 

We  may  conclude  that  for  every  disease  of  intestinal 
source,  the  most  convenient  and  efficacious  method  of  vac- 
cination would  be  the  prolonged  ingestion  of  dead  bacteria, 
while  the  most  efficacious  method  of  treatment  would  be 
specific  bacterial  therapy  by  fractionated  intravenous 
injections. 


I 


CHAPTER  IV. 
MECHANISM  OF  INFECTION. 

Infection  or  Contagion — Virulence — Immunity — Refractory  State, 

We  may  deduce  from  what  has  preceded  that,  if  vacci- 
nations, either  spontaneous  or  artificial,  can  increase  the 
resistance  of  the  organism  against  spontaneous  infection 
by  increasing  within  certain  limits  the  parenteral  digestive 
power  and  probably  also  the  digestive  power  of  the  intestines : 
for  the  cells  of  the  mucosa  and  of  the  intestinal  glands  may 
quite  as  well  as  those  of  other  tissues  and  organs  participate 
in  the  production  of  antibodies  and  distribute  them  partly 
into  the  circulation  and  partly  into  the  intestinal  contents; 
they  (vaccinations)  may  at  the  same  time  increase  the  sus- 
ceptiblity  of  the  organism  to  the  reaction  of  albumins  and 
thus  put  the  organism  into  a  state  which  we  may  rightly 
call  ''anaphylactic." 

If  then,  as  seems  probable,  bacteria  of  the  colon-typhoid 
group  as  well  as  cholera  vibrios  do  not  secrete  a  toxin- 
antigen  of  a  crystalloid  poison,  diseases  caused  by  these 
bacteria  are  nothing  else  than  anaphylactic  crises,  whose 
violence  and  duration  is  determined  by  the  total  of  conditions 
which  we  have  analyzed  above. 

In  typhoid  fever  these  crises  may  last  for  several  weeks 
and  there  is  not  one  single  crisis  but  a  series  of  successive 
crises.  Paratyphoid  may  develop  in  the  same  way  as 
typhoid  or  much  more  quickly  (in  one  or  a  few  days)  accord- 
ing to  the  state  of  sensitiveness  of  the  subject  and  the  dose 
of  bacteria  injected  and  the  differences  of  development 
depend  principally  upon  differences  in  the  rapidity  with  which 
bacteria  multiply.  Cholera  develops  always  very  rapidly, 
because  the  bacteria  rapidly  yield  very  abundant  cultures 
and  also  because  bacteriolysis  takes  place  rapidly.     Colon 


J 


MECHANISM  OF  INFECTION  75 

bacilli  only  rarely  become  pathogenic,  because  the  digestion 
of  the  bacterial  body  and  the  products  of  bacteriolysis  ought 
to  be  complete  in  the  intestine. 

A  true  and  lasting  immunity  would  consist  in  rendering 
the  organism  refractory  to  anaphylactic  hypersusceptibility; 
that  is  to  say,  to  render  the  organism  capable  of  completely 
digesting  bacteria  or  products  of  bacteriolysis  in  the  stomach 
and  intestines  so  as  to  hinder  these  products  from  penetrat- 
ing in  the  form  of  specific  colloids  into  the  blood  as  well  as 
into  the  cells  of  the  mucosa  and  of  the  intestinal  glands. 

Some  experiments  on  mouse  typhoid  permit  the  hope  that 
this  will  be  not  impossible  of  accomplishment.  One  may 
demonstrate  that  if  some  or  rather  some  dozens  of  bacteria 
are  necessary  to  infect  an  animal  by  subcutaneous  injection, 
several  thousand  times  as  many  are  necessary  to  infect  an 
animal  by  the  ingestion  of  a  pure  culture  and  several  millions 
if  this  pure  culture  is  mixed  with  another  substance  of 
whatever  nature. 

If  then,  after  having  determined  the  minimum  lethal 
dose  by  ingestion  of  a  pure  culture,  the  animal  is  treated 
during  and  after  by  hypodermic  injections  of  sodium  caco- 
dylate  or  calcium  glycerophosphate  in  convenient  doses,  it 
is  found  that  the  animal  thus  treated  resists  doses  which 
are  very  fatal  for  controls.  It  is  also  found  that  animals 
treated  in  this  way  are  not  vaccinated  and  have  no  specific 
antibodies  in  their  blood  which  proves  that  the  bacteria 
or  their  antigens  have  not  been  able  to  penetrate  into  the 
interior  and  that  they  have  been  very  probably  digested  in 
the  stomach  and  intestines,  or  perhaps  evacuated  without 
havings  been  attacked  by  digestion. 

From  another  aspect  it  is  possible  to  determine  by  a 
series  of  tests  that  the  same  paratyphoid  pathogenic  for 
mice  and  completely  harmless  in  the  beginning  for  Mus 
Decumanus  and  Mus  Rattus  can  little  by  little  become 
more  and  more  pathogenic  for  these  species  by  ingestion 
as  a  result  of  a  series  of  alternate  passages:  (1)  In  vitro 
in  a  broth  culture  prepared  with  the  flesh  of  the  animals  of 
this  species;  and  (2)  in  collodion  sacs  inclosed  for  twenty- 
four  hours  in  the  peritoneal  cavity  of  these  animals.     Cul- 


76  MECHANISM  OF  INFECTION 

tures  are  finally  obtained,  of  which  a  small  dose  will  kill 
by  ingestion  field  and  white  mice  in  four  to  six  days  and 
rats  in  six  to  twelve  days. 

These  cultures  have  been  preserved  in  sealed  ampoules  for 
one  to  ten  years  and  tested  as  to  their  virulence  once  to 
twice  a  year.  They  have  always  preserved  their  virulence 
and  have  even  become  a  little  more  pathogenic  for  mice, 
but  at  the  same  time  they  lose  their  virulence  for  rats,  so 
that  after  ten  years  they  have  become  completely  avirulent 
for  these  animals.  By  passing  a  culture,  virulent  for  the  two 
species,  through  ordinary  broth,  the  virulence  for  the  rats 
remains  constant  for  one  or  two  years,  but  finally  diminishes 
and  almost  disappears  at  the  end  of  a  longer  or  shorter 
time.    Thus  we  conclude: 

1.  That  the  bacterial  substance  virulent  for  mice  is 
difi^erent  from  that  which  is  virulent  for  rats. 

2.  That  the  bacteria  can  produce,  augment  and  lose 
this  specific  pathogenicity  substance. 

3.  That  this  property  is  progressively  acquired  by  being 
nourished  with  the  "substance  rat"  and  that  it  is  lost 
when  not  nourished  in  this  way. 

By  analyzing  these  facts  we  are  obliged  to  assume  that 
in  order  to  nourish  itself  with  the  "substance  rat,"  the 
bacteria  has  been  obliged  to  learn  to  fix  this  substance  by 
a  special  chemical  affinity,  and  the  fact  that  the  bacteria 
can  multiply  this  fixation  substance,  even  when  trans- 
planted into  a  non-specific  nutritive  medium,  obliges  us  to 
assume  that  the  fixation  is  intracellular. 

Thus,  in  the  last  analysis,  the  substance  of  the  bacteria 
acquires  a  specific  affinity  for  the  "substance  rat"  and  it  is, 
thanks  to  this  acquired  affinity,  that  the  bacteria,  or  more 
exactly,  its  own  specific  substance,  can  fix  and  digest  the 
"substance  rat"  and  render  it  assimilable. 

But  it  is  evident  that  affinities  ought  to  be  always  recipro- 
cal and  that  in  consequence  the  fixing  substance  of  the 
bacteria,  freed  by  bacteriolysis,  can  fix  itself  by  the  same 
affinity  and  produce  reactions  of  the  same  nature  in  an  extra- 
or  intracellular  substance  of  the  rat  when  it  finds  itself  in 
the  organism  of  this  animal. 


MECHANISM  OF  INFECTION  77 

The  '^  substance  rat"  may  thus  be  considered  Hke  an  anti- 
gen for  paratyphoid  and  this  antigen  provokes  the  formation 
of  an  antibody  exactly  in  the  same  way,  and  by  the  same 
mechanism,  as  the  fixing  substance  of  the  bacteria  becomes 
antigenic  for  the  rat  and  produces  in  the  organism  of  the 
rat  the  formation  of  a  specific  antibody. 

We  may  assume  that  bacteria  become  pathogenic  for  an 
animal  species  exactly  in  the  same  way  as  the  organism  of 
these  species  becomes  in  its  turn  pathogenic  for  the  bacteria. 
The  procedure  which  we  have  employed  for  rendering  para- 
typhoid, which  is  primarily  pathogenic  only  for  field  mice, 
virulent  for  rats  does  not  apply  only  to  this  particular  case. 

Dujardin  and  Beaumetz  have  rendered  virulent,  for 
sheep  and  goats,  a  culture  of  pleuropneumonia  which  had 
been  considered  as  pathogenic  exclusively  for  cattle,  by 
cultivating  the  bacteria  of  this  disease  in  incompletely 
digested  mutton  broth,  and  we  know  from  Pasteur  that 
anthrax  may  become  avirulent  and  may  re-acquire  its  lost 
virulence  by  passages  through  more  sensitive  animals.  We 
know  that  the  bacillus  of  tuberculosis  may  lose  its  virulence 
after  a  long  series  of  passages  in  exclusively  crystalloid 
media,  and  that  the  tubercle  germ  of  cold-blooded  animals 
is  entirely  harmless  for  the  guinea-pig,  but  may  become 
pathogenic  for  this  animal  by  appropriate  cultures  and 
passages. 

The  processes  may  vary  for  each  particular  case  in  their 
details,  but  the  principle  ought  to  be  a  general  one  and 
should  apply  to  all  living  beings.  The  indispensable  condi- 
tion under  which  bacteria  can  become  pathogenic  and 
under  which  an  organism  can  produce  a  specific  antibody 
consists  in  penetration  into  the  interior  of  the  bacteria  or 
into  the  interior  of  the  organism  of  a  substance  in  colloidal 
state,  that  is  to  say,  incompletely  digested,  whose  digestion 
can  be  completed  by  the  cell.  Thus,  bacteria  which  are 
completely  transformed  into  amino-acids  by  gastro-intestinal 
digestion  cannot  become  pathogenic,  nor  can  bacteria 
nourished  exclusively  by  the  amino-acids  split  off  from 
animal  albumins  become  pathogenic  for  this  animal. 

The  study  of  bacteriolysis  in  anthrax  as  well  as  the  study 


78  MECHANISM  OF  INFECTION 

of  the  evolution  of  anthrax  in  the  white  rat  has  given  us  the 
most  interesting  side  lights  on  the  nature  of  the  reciprocal 
relations  between  bacteria  and  organism.  We  know  by  the 
studies  of  Savtchenko  that  anthrax  bacilli  are  very  rapidly 
destroyed  in  rat  sera.  However,  by  starting  the  first 
cultures  in  a  mixture  of  a  very  small  quantity  of  serum  with 
a  large  quantity  of  ordinary  bouillon,  and  by  continuing 
passages  through  mixtures  containing  relatively  larger  and 
larger  quantities  of  serum,  we  finally  obtain  a  fairly  abund- 
ant culture  in  pure-rat  serum;  that  is,  we  obtain  a  race  of 
bacteria  which  resists  the  destructive  action  of  this  serum. 
If  we  again  transplant  this  race  into  ordinary  bouillon  and 
if  we  make  several  transplants  in  it,  we  find  that  even  in 
spite  of  the  change  in  media,  that  the  properties  of  serum 
resistance  are  obtained. 

If  one  of  these  twenty-four-hour  cultures  is  filtered  through 
a  porcelain  bougie  so  as  to  completely  remove  the  bacteria 
and  if  a  small  amount  of  the  filtrate  is  added  to  rat  serum, 
and  this  mixture  is  added  to  broth  which  is  then  inoculated 
with  a  non-serum-resistant  strain,  a  growth  will  be  obtained 
quite  as  abundant  as  in  ordinary  broth.  Anthrax  bacilli 
can  thus  acquire  the  ability  little  by  little  to  fix  and  digest 
rat  serum  by  increasing  the  quantity  of  a  "fixing  substance." 
The  ability  to  produce  this  substance  is  retained  even  when 
there  is  no  longer  any  rat  serum  to  stimulate  it.  The  excess 
given  off  to  the  exterior  and  when  added  to  rat  serum,  can 
neutralize  in  vitro  the  bactericidal  properties  of  the  serum, 
and  again  render  it  all  the  more  assimilable  for  a  non-serum- 
resistant  race.  Finally  a  filtered  broth  culture  originating 
from  a  non-serum-resistant  culture  mixed  in  equal  propor- 
tions with  rat  serum  will  hinder  the  bactericidal  action  of 
the  latter,  but  in  a  much  less  degree. 

Anthrax  bacilli  can  produce  then  a  specific  antibody 
under  different  conditions,  but  by  the  same  process  as  para- 
typhoid as  studied  above.  Moreover,  contrary  to  suppo- 
sition, a  culture  of  anthrax  avirulent  for  rats  does  not 
become  virulent  when  rendered  serum-resistant;  so  that  we 
must  conclude  that  it  is  not  by  acquiring  an  affinity  for 
any  animal  substance  that  a  bacterium  can  become  patho- 
genic for  the  animal,  and  that  it  is  not  by  virtue  of  its 


MECHANISM  OF  INFECTION  79 

combination  with  this  substance  or  with  all  the  bactericidal 
substances  in  rat  serum  that  bacteria  become  pathogenic 
for  these  animals. 

What  proves  this  is  that,  in  spite  of  the  bactericidal 
property  of  their  serum,  rats  do  not  generally  resist  a 
virulent  inoculation  of  anthrax.  Another  peculiarity,  all 
the  more  important  from  this  point  of  view  is  that  when 
a  rat  has  resisted  a  primary  inoculation  it  becomes  more 
sensitive  to  a  second  inoculation  of  the  same  virus.  It 
happens  sometimes  that  an  animal  can  resist  three  or  four 
successive  injections  and  succumbs  only  to  the  fifth.  There 
is  here  a  collection  of  facts  which  could  not  be  correlated 
and  which  puzzled  bacteriologists  of  the  period  of  1889-1890. 
It  was  not  known  by  what  mechanism  bacteria  might 
become  pathogenic  for  an  animal.  Today  this  mechanism 
can  be  explained  in  the  following  way: 

Rats  in  general,  especially  white  rats,  resist  virulent 
inoculations  of  anthrax  better  than  all  the  other  test  animals 
and  they  owe  this  relative  resistance  to  the  more  or  less 
marked  bactericidal  properties  of  their  plasma.  If  the  dose 
is  not  too  large  the  bacteria  are  destroyed  by  bacteriolysis 
and  by  phagocytes  before  being  able  to  develop  into  a  more 
resistant  race  and  the  rat  recovers.  But  although  the 
living  bacteria  may  disappear  in  this  way  products  of 
bacteriolysis  remain  in  the  organism.  The  products  pro- 
voke the  formation  of  specific  antibodies  which  are  not 
bacteriolytic,  but  which  neutralize  a  certain  quantity  of  the 
normal  bacteriolytic  substance  of  the  organism.  The  same 
phenomenon  is  seen  in  vitro  when  the  same  tube  of  serum 
is  mixed  several  times.  The  second  or  third  mixing  will 
give  a  culture. 

Something  happens  here  very  analogous  to  what  we  have 
seen  in  the  first  stage  of  typhoid  infection  when  bacterial 
products  are  incompletely  digested  in  the  stomach  and 
intestines,  and  have  penetrated  into  the  blood  and  into 
the  cells  of  the  intestinal  mucosa,  and  by  the  formation  of 
an  antibody,  have  rendered  the  organism  more  sensitive  to 
bacterial  invasion.  The  bacteria  of  the  second  injection 
will  thus  resist  better  and  longer  the  bactericidal^  properties 
of  the  organism;  their  more  rapid  multiplication  will  sue- 


80  -        MECHANISM  OF  INFECTION 

cessfully  resist  destruction  and  each  successive  generation 
will  be  more  resistant  to  bacteriolysis.  At  the  same  time 
the  compounds  of  the  bacterial  products  with  antibodies 
will  cause  the  formation  of  more  and  more  severe  lesions. 
Infections,  at  first  local,  may  become  generalized  and  the 
animal  may  die. 

The  numerous  experiments  of  Loeffler,  Behring,  Metchni- 
koff  and  others  on  anthrax  in  rats  do  not  give  us  a  sufficiently 
accurate  explanation  of  all  the  conditions  of  the  evolution 
of  this  disease  in  animals,  because  all  their  experiments 
were  in  reply  to  other  questions  which  need  not  occupy  us 
here.  But  such  as  they  are,  they  permit  us  to  conclude  that 
hypersensitization  of  the  white  rat  to  anthrax,  by  one  or 
several  inoculations  which  may  be  considered  as  vaccina- 
tions, is  not  in  contradiction  to  the  principle  of  vaccination 
which  makes  no  exception  for  anthrax  in  animals  nor  for 
any  other  known  septicemic  infection. 

Relapses  in  typhoid,  auto-reinfections  in  tuberculosis 
and  syphilis,  reinfections  in  cyclic  diseases  (malaria,  try- 
panosomiasis) and  all  the  chronic  infections  in  which  attacks 
alternate  with  more  or  less  prolonged  remissions  (gonorrhea, 
infiuenza)  are  all  phenomena  of  the  same  category.  They 
all  presuppose  a  certain  reciprocal  adaptation  or  a  symbiosis 
of  the  parasites  and  the  organism:  The  difference  in  the 
observed  results,  that  is  to  say,  the  increase  or  diminution  of 
resistance  or  of  sensitization  of  the  parasite  or  the  organism, 
the  final  destruction  of  one  or  the  other  are  determined  only 
by  secondary  factors,  notably:  By  the  degree  of  reciprocal 
adaptation  of  the  parasite  and  the  organism  at  the  moment 
of  infection;  by  the  infecting  dose;  by  the  general  condition 
of  the  organism  before  the  infection  and  the  severity  of 
the  lesions  which  are  produced  during  the  period  of  disease 
or  during  the  attacks.  The  mechanism  of  these  reactions 
will  be  under  all  circumstances  the  same. 

Resume  and  Conclusions. 

1,  A  yathologic  state  can  be  caused  only  by: 
(a)  The  penetration  into  the  interior  of  the  organism  of 
bacteria  or  of  bacterial  products  in  a  colloidal  state. 


MECHANISM  OF  INFECTION  81 

(b)  The  existence  in  the  organism  of  chemical  affinities  for 
these  bacterial  products. 

2.  Infection  or  contagion  is  brought  about  by  the  pene- 
tration of  bacteria  or  colloidal  bacterial  products  across 
the  mucous  membranes  of  the  digestive  or  respiratory- 
apparatus  or  by  means  of  intra-  or  hypodermic  inoculations. 

3.  Incubation  in  infection  is  the  time  necessary  for  a 
bacterium  with  the  products  of  its  secretion  or  bacteriolysis 
to  adapt  itself  to  its  medium  and  to  cause  in  the  organism 
the  formation  of  specific  antibodies  in  excess. 

4.  The  preexistence  of  antibodies  in  certain  organisms  for 
certain  bacteria  can  be  explained: 

(a)  By  heredity,  and 

(6)  By  individual  spontaneous  vaccinations. 

5.  The  formation  of  normal  antibodies,  or  in  other  words, 
specific  affinities,  when  they  do  not  preexist,  can  be  explained 
by  the  infection  itself,  or,  in  other  words,  by  the  penetration 
into  the  interior  of  the  organism  of  colloidal  bacterial  pro- 
ducts in  immunizing  doses  during  the  incubation  period. 
In  this  case  the  bacterium  itself  will  create  the  affinity. 

6.  Every  bacterium  which  can  adapt  itself  to  an  animal 
medium,  that  is  to  say,  which  can  digest  and  assimilate 
certain  animal  substances  in  the  colloidal  state,  can  become 
pathogenic  for  that  animal. 

7.  The  state  of  resistance  on  ingestion  to  bacteria  when 
ingested  is  due  to  the  complete  digestibility  of  all  bacteria 
and  all  their  products  by  gastro-intestinal  digestion. 

The  state  of  resistance  on  inoculation  results  from  the 
absolute  inability  of  the  bacteria  to  be  nourished  in  the 
animal  medium. 

8.  Active  immunity  is  a  state  of  resistance  of  the  organism 
to  a  certain  dose  of  infecting  bacteria  which  is  rapidly  and 
easily  digestible.  It  will  be  complicated  by  an  anaphy- 
lactic hypersensitiveness  whenever  the  compound  of  antigen  . 
with  antibody  in  excess  is  insoluble,  and  therefore,  more 
or  less  difficult  to  digest.  There  will  be  no  hypersensitive- 
ness when  this  compound  is  soluble  and  neutral. 


CHAPTER  V. 
IMMUNITY  AND  ANAPHYLAXIS. 

If  we  analyze  the  total  of  studies  accumulated  to  the 
present  time  on  immunity  and  anaphylaxis  we  may  isolate 
a  certain  number  of  facts  which  we  will  review  as  briefly 
as  possible  with  the  interpretations  which  have  been  given 
them.  But  first  let  us  see  if  it  is  possible  to  separate  from 
the  total  facts  a  general  idea  which  will  explain  the  nature 
and  the  mechanism  of  the  reactions  which  determine  the 
different  phases  of  evolution  of  the  infectious  diseases  and 
of  the  various  pathologic  states  no  matter  whether  these 
states  are  caused  by  animal  or  vegetable  albumins  con- 
sidered as  normally  toxic,  such  as  venins,  the  serum  of 
eels  and  turtles,  ricin,  abrin,  etc. ;  by  synthetic  colloids  such 
as  the  arsenobenzenes;  or,  finally,  by  albumins  considered 
as  exclusively  nutritious  when  they  penetrate  into  the  internal 
substance  of  the  organism  by  the  intestines  after  complete 
digestion,  but  which  provoke  anaphylactic  states  when 
made  to  penetrate  into  this  interior  by  subcutaneous,  intra- 
venous or  even  intrarectal  injections. 

We  have  not  failed  to  notice  how  difficult  it  is  to  define  the 
limits  between  the  different  groups  of  substances  just  enum- 
erated. Thus,  a  certain  number  of  toxic  albumins  or  of 
pathogenic  bacteria  may  be  absorbed  by  mouth  without 
causing  symptoms,  others  remain  pathogenic  after  having 
undergone  gastric  and  intestinal  digestion.  All  possess  a 
certain  number  of  characteristics  in  common  and  the  value 
"of  these  characteristics  for  any  classification  whatever 
will  always  furnish  material  for  endless  discussions.  It  is 
necessary  to  note  that  the  distinctions  indicated  above  and 
now  made  again  have  no  absolute  value  and  that  they 
are  made  only  provisionally  for  the  clarity  of  the  discussion 
which  follows. 


I 


IMMUNITY  AND  ANAPHYLAXIS  83 

We  have  then  the  following  facts: 

1.  The  toxins  of  tetanus  and  diphtheria  may  be  injected 
into  sensitive  animals  in  non-toxic  or  toxic  doses  and  then: 

(a)  Each  injection  of  a  non-toxic  or  slightly  pathogenic 
dose  protects  the  injected  animal  after  a  certain  incubation 
period  against  a  larger  dose:    active  immunity. 

(b)  The  serum  of  the  animal  thus  actively  immunized 
will  neutralize  the  pathogenic  action  of  thfe  toxin  in  vitro, 
and  if  injected  prophylactically  into  a  new  animal  will  protect 
this  animal  against  a  pathogenic  dose :  passive  immunity. 

(c)  The  injection  of  toxic  mixtures  of  toxins  with  their 
antitoxins  as  well  as  the  preventive  injections  of  "anti" 
sera  from  animals  of  the  same  species  never  causes  ana- 
phylactic disturbances. 

Thus  for  tetanus  and  diphtheria  toxins  there  is  active  and 
passive  immunity;  but  there  is  never  anaphylaxis,  either  active 
or  passive. 

2.  Living  pathogenic  bacteria  may  be  easily  injected  in 
non-pathogenic  doses,  but  in  the  technic  of  vaccinations  it 
is  convenient  to  employ  either  living  cultures  with  attenu- 
ated virulence,  or  bacterial  bodies  killed  by  heat  or  other 
procedures  or  filtered  broth  cultures  without  bacteria. 
The  injection  of  all  these  products  in  non-pathogenic  doses 
provokes  in  part  reactions  of  the  same  nature  as  in  the 
preceding  section,  that  is  to  say: 

(a)  An  active  anti-infectious  immunity  in  the  treated 
animal. 

(6)  The  serum  of  the  treated  animal  can  confer  a  passive 
immunity  on  a  normal  animal  but  at  the  same  time  this 
same  treatment  has  caused 

(c)  A  state  of  active  anaphylaxis  in  the  treated  animal 
and  the  serum  of  this  animal  has  become  able  to  transfer 
passively  anaphylaxis  to  a  new  animal. 

Thus,  for  all  living  or  dead  pathogenic  bacteria  as  well 
as  for  their  filtered  broth  cultures  there  is  at  one  and  the 
same  time  active  and  passive  anti-infectious  immunity  and 
active  and  passive  anaphylaxis. 

3.  Pathogenic  albumins  behave,  from  the  point  of  view  of 
their    immunizing    or   anaphylactic   reactions,   exactly   the 


84  IMMUNITY  AND  ANAPHYLAXIS 

same  way  as  pathogenic  bacteria  and  it  is  natural  that  it 
should  be  so,  because  bacteria  can  act  only  through  their 
soluble  products  of  secretion  or  through  bacteriolysis. 
There  is  at  once  antitoxic  immunity  and  anaphylactic  sen- 
sitization, active  and  passive. 

4.  For  exclusively  nutritive  albumins  there  can  be  no  active 
and  passive  immunity,  but  there  is  active  and  passive  ana- 
phylaxis. 

All  these  substances  have  a  common  property.  Injections 
of  them  into  a  normal  animal  in  non-  or  slightly  pathogenic 
doses  always  causes  a  reaction  of  the  same  nature:  the 
formation  of  an  antibody  which  is  specific  without  being 
always  exclusively  specific.  They  are  all  grouped  under 
the  name  of  antigens.  The  substances  which  are  formed 
in  the  organism  by  these  antigens  and  which  possess  a 
special,  if  not  always  exclusive,  affinity  for  the  corresponding 
antigens  are  called  antibodies. 

In  attempting  to  define  the  physicochemical  properties  of 
antigens,  it  is  recognized  that  they  are  always  albumins  or 
colloids;  as  to  antibodies  it  is  not  possible  to  isolate  them 
from  the  albumins  of  the  serum  in  which  they  are  found. 
They  should  be  considered  as  colloids  or  at  least  having 
an  action  like  colloidal  action. 

All  albumins  are  not  ''antigens."  This  property  belongs 
only  to  albumins  called  heterologous  while  homologous 
albumins — that  is,  belonging  to  the  individual  of  the  same 
species — do  not  produce  the  formation  of  antibodies,  and 
therefore  do  not  produce  anaphylaxis.  The  reaction  which 
causes  the  formation  of  antibodies  and  which  confers  immun- 
ity alone,  or  both  immunity  and  anaphylaxis,  or  finally 
anaphylaxis  alone,  is  not  determined  solely  by  the  physico- 
chemical  nature  of  antigens  since  homologous  albumins  are, 
from  this  point  of  view,  identical  with  heterologous  albu- 
mins. This  reaction  depends  upon  the  state  of  the  treated 
organism  with  reference  to  the  injected  antigen. 

For  example,  an  organism  strongly  (actively)  immun- 
ized against  tetanus  or  diphtheria  toxin  will  react  in  the 
same  way  to  a  second  dose  of  one  of  these  toxins  as  a  normal 
organism  would  react  to  a  homologous  albumin.     In  other 


IMMUNITY  AND  ANAPHYLAXIS  85 

words,  the  transformation  by  which  toxins  and  albumins 
after  injection  become  either  assimilated  or  eliminated  is 
accomplished  by  a  reaction  of  the  same  nature. 

It  is  hardly  probable  that  an  albumin,  even  homologous, 
when  injected  into  the  blood  or  under  the  skin  can  be  assimil- 
ated without  undergoing  some  sort  of  transformation  and 
the  mild  anaphylactic  disturbances  which  are  seen  after 
the  transfusion  of  100  c.c.  or  200  c.c.  of  whole  blood:  chills, 
excitement,  dyspnea,  peripheral  pallor  seem  to  show  that 
in  this  case  there  is  no  assimilation  without  previous  trans- 
formation. In  every  normal  organism  there  is  an  antibody 
in  excess  for  homologous  albumins  and  this  antibody  reacts 
with  these  albumins  in  a  way  quite  analogous  to  the  reac- 
tion of  toxin  with  antitoxin. 

We  will  return  later  to  this  question  which  we  can  only 
indicate  here.  For  the  moment  it  is  important  to  recall 
from  what  has  preceded,  that  if  the  nature  of  the  reactions 
caused  by  antigens  seems  to  be  determined  by  the  physico- 
chemical  properties  of  the  colloidal  state  of  these  substances, 
the  effects  of  these  reactions  on  the  organism  will  depend 
principally,  if  not  exclusively,  on  the  nature,  the  biologic 
properties  and  the  quantity  of  antibodies,  normal  or  in  excess. 

From  the  biologic  point  of  view,  we  may  divide  the  reac- 
tions between  antigen  and  antibodies  into  two  great  groups: 

1.  Those  which  produce  immunity  alone— diphtheria, 
tetanus  toxins,  perhaps  botulism  and  homologous  albumins. 

2.  Those  which  produce  immunity  and  anaphylaxis  or 
only  anaphylaxis— all  the  other  antigens,  bacteria  and 
heterologous  albumins. 

From  the  physicochemical  point  of  view  it  may  be  said 
that: 

1.  Antigens  which  are  exclusively  immunizing  form  with 
their  antibodies  soluble  compounds. 

2.  Those  which  are  immunizing  and  anaphylactic  or 
exclusively  anaphylactic  form  with  their  antibodies  insoluble 
compounds. 

In  the  first  instance  the  antibodies  in  excess  dissolve  the 
colloidal  antigens;  in  the  second,  they  precipitate  and  this 
difference  in  the  nature  of  the  resulting  compounds  is  of  the 


86  IMMUNITY  AND  ANAPHYLAXIS 

greatest  importance  from  the  biologic  point  of  view  as  well 
as  from  the  point  of  view  of  evolution  of  pathologic  states. 

When  antibodies  form  with  their .  antigens  soluble  com- 
pounds, the  appearance  of  antibodies  in  excess  coincides 
with  the  cure.  But  in  all  the  other  cases  when  insoluble 
compounds  are  formed,  the  appearance  of  antibodies  in 
excess  always  coincides  with  the  beginning  of  the  disease 
period  or,  in  other  words,  with  the  first  appreciable  patho- 
logic symptoms. 

Up  to  the  present  we  have  had  no  idea  of  considering  these 
reactions  together  and  in  detail.  There  is,  to  be  sure,  a 
theory  (Ehrlich)  to  explain  the  origin  of  the  pathologic 
state  or  the  recovery  in  diseases  caused  by  the  true  toxins 
(diphtheria  and  tetanus).  It  was  assumed  generally  that 
in  the  other  infectious  diseases  the  different  aspects  of  the 
pathologic  state  were  caused  by  the  combination  of  differ- 
ent bacteria  and  by  exo-  and  endotoxins  produced  in  the 
organism  by  these  bacteria  without  attempting  to  explain 
the  mechanism  of  the  reactions.  After  Ch.  Richet,  several 
theories  were  formulated  to  explain  the  nature  and  the 
mechanism  of  anaphylactic  reactions  but  without  attempt- 
ing to  explain  the  exact  nature  of  the  origin  of  these  reactions. 

And  although  clinicians  have,  at  one  time  or  another, 
called  attention  to  "anaphylactic  syndromes"  in  some  infec- 
tious diseases  (Ivanoif  in  malaria)  or  to  "  anaphylactic  crises," 
following  the  injection  of  certain  drugs  (iodine,  antipyrin, 
arsenobenzene)j  the  true  students  of  anaphylaxis  could  see 
only  superficial  or  accidental  analogies  because  these  ana- 
phylactic crises  were  not  produced  under  the  same  conditions 
as  in  their  experiments. 

But  we  have  seen  that  immunizing  or  anaphylactic  reac- 
tions with  production  of  antibodies  can  be  provoked  only 
by  colloids  and  that  crystalloids  never  cause  analogous 
reactions,  because  an  antigenic  albumin  loses  its  antigenic 
properties  at  the  time  when  it  ceases  to  be  a  colloid,  that  is 
to  say,  when  it  is  transformed  into  free  amino-acids.  The 
nature  of  all  these  reactions  ought  thus  to  be  sought  in 
the  colloidal  state  of  antigens  and  it  is  only  by  attempting 
to  analyze  the   physicochemical   properties  of  colloids  as 


ANAPHYLAXIS  87 

well  as  the  transformations  which  these  substances  undergo 
in  the  interior  of  the  organism  that  it  will  be  possible  to 
discover  why  the  organism  is  obliged  to  produce  antibodies  in 
excess,  what  the  role  of  these  antibodies  is  and  what  the 
nature  of  the  reaction  between  antibodies  and  antigens. 

These  reactions  can  be  reduced  to  three  different  types 
which  we  have  treated  in  detail  in  the  preceding  chapter: 
The  evolution  of  diphtheria,  of  tuberculosis  and  of  typhoid 
fever.  These  types  differ  among  themselves  according  to 
the  primary  and  secondary  action  of  the  antigen  on  the 
organism  and  to  the  action  of  the  antibody  in  excess  on  the 
antigen. 

These  differences  can  be  reviewed  in  a  few  words :  In  diph- 
theria the  antigen  acts  directly  on  the  tissues  and  the  anti- 
body in  excess  neutralizes  the  antigen  without  precipitating 
it.  The  appearance  of  the  antigen  in  excess  coincides  with 
recovery.    There  is  no  anaphylaxis. 

In  tuberculosis  and  in  typhoid  the  antigen  is  not  directly 
toxic.  In  these  cases  the  antigen  is  not  an  exotoxin  as  in 
diphtheria,  but  is  the  albumin  of  the  bacterial  body  w^hose 
pathogenic  action  on  the  organism  is  manifested  only  by  the 
appearance  of  antibody  in  excess.  The  antigen  (bacillin) 
forms  with  antibody  in  excess  insoluble  compounds.  All  the 
symptoms  of  the  disease  are  anaphylactic  in  nature. 

ANAPHYLAXIS. 

The  study  of  the  pathogenicity  of  infectious  diseases 
has  led  us  irresistably  through  a  series  of  logical  deductions 
drawn  from  exact  experiments  to  the  conception  that  the 
pathologic  manifestations  in  disease  are  exclusively  ana- 
phylactic in  nature. 

To  explain  the  nature,  the  mechanism  and  the  basis  of 
anaphylaxis  demands  a  knowledge  of  the  nature  of  all  the 
septicemic  diseases,  and  a  general  idea  of  all  the  researches 
concerning  these  diseases.  Let  us  see  w^hat  this  knowledge 
includes: 

To  Charles  Richet,  to  w^hom  belongs  the  credit  for  the 
discovery  of  the  biologic  importance  of  the  subject  and  of 


88  .  IMMUNITY  AND  ANAPHYLAXIS 

the  word,  "anaphylaxis"  was  a  state  of  hyperseiisitiveness 
in  which  an  organism  found  itself  as  a  result  of  a  series  of 
preparatory  injections  of  an  antigen.  The  same  antigen, 
non-  or  very  slightly  toxic  in  the  first  injection  was  very 
toxic  in  the  second  or  "shock"  injection  and,  according  to 
Richet,  this  toxicity  resulted  from  the  formation  of  a  particu- 
lar poison  "apotoxin"  which  was  formed  by  the  combination 
of  the  antigen  with  a  hypothetical  "toxogenine." 

According  to  Besredka  there  is  no  poison  in  anaphylactic 
hypersensitiveness.  He  said,  some  years  ago  (1907),  "In  a 
general  way,  the  majority  of  the  reported  facts  seem  to 
indicate  that  the  formation  of  anaphylaxis  and  of  anti- 
anaphylaxis  may  be  reduced  to  the  actions  of  precipitation 
and  absorption  which  resist  the  reactions  of  colloids  between 
themselves."  He  had,  as  he  said  in  a  quite  recent  work,^ 
"  A  single  purpose ;  to  contrast  the  idea  of  a  physical  process 
with  that  of  a  poison  determined  chemically." 

Finally,  after  having  analyzed  with  clarity  and  customary 
ability  the  numerous  studies  of  P^riedberger,  Neufeld  and 
Dold,  Doerr  and  Russ,  Levaditi  and  Mutermilch,  Bordet, 
Kraus,  Nicolle,  Vaughan  and  Wheeler  and  others  and 
selected  the  theories  of  these  authors,  whether  chemical 
or  physical,  Besredka  completed  his  first  conception  by 
saying,  "What  dominates  anaphylaxis  and  anti-anaphylaxis 
is  neither  poison  nor  antipoison  but  it  is  on  the  one  hand 
the  rapidity  with  which  the  union  of  '  sensibiligen'  and  '  sen- 
sibilisin'  takes  place  and,  on  the  other  hand,  the  site  of  this 
union  which  is  probably  the  nervous  system." 

The  causes  of  the  crises  of  anaphylactic  shock  are  then, 
according  to  Besredka,  partly  physical;  at  all  events  we 
read  a  few  lines  further  in  the  same  work  (page  142): 
"What  happens  after  the  test  injection?  The  new  antigen 
meets  the  sensibilisin  already  transformed.  Their  affinity 
results  in  an  intense  reaction.  Whether  this  reaction  rup- 
tures the  equilibrium  of  certain  nervous  cells  in  which  the 
combination  takes  place  or  whether  it  is  accompanied  by 
a  loss  or  by  an  absorption  of  caloric  or  other  energy,  there 

^  Anaphylaxis  et  Anti-anaphylaxie,  Masson  et  cie.  ed.  Paris,  1917. 


ANAPHYLAXIS  89 

takes  place  a  series  of  phenomena  always  the  same,  which 
constitutes  anaphylactic  shock." 

Besredka  does  not  explain  either  by  physical  or  by  chemi- 
cal means  or  by  both  together  the  affinities  and  combina- 
tions which  he  considers  take  part  in  the  reaction,  but  the 
apparent  contradiction  expressed  in  the  two  phrases  which 
precede  may  be  explained  with  a  little  latitude.  The  affin- 
ities are  very  probably  chemical  in  nature  and  the  combi- 
nations as  well;  but  in  Besredka's  conception  the  product 
formed  by  the  combination  does  not  act  by  its  chemical 
properties  (poison),  but  only  by  its  physical  properties 
(precipitate).  It  is  not  the  product  already  formed  which 
causes  the  pathologic  manifestations  of  the  anaphylactic 
state,  but  only  the  rapidity  with  which  products  are  formed ; 
in  his  opinion,  precipitates  are  not  necessary. 

Thus,  in  the  last  analysis  whether  a  precipitate  is  formed 
or  not,  the  experiments  of  Besredka  and  the  intrepretations 
which  he  himself  puts  on  them  indicate  that  it  is  the  factor 
time  which  is  at  least  one  of  the  conditions  of  the  reaction, 
and  may  be  the  single  cause  of  anaphylactic  shock.  (This 
one  factor  ought,  we  think,  to  be  chemical  or  rather  physico- 
chemical  since  the  reaction  concerns  colloids.) 

F.  G.  Novy  and  P.  H.  de  Kruif^  return  again  in  an  exten- 
sive work  which  has  just  appeared,  to  the  idea  of  a  soluble 
anaphylatoxin  or  ''taraxin"  formed  in  the  organism  by  a 
substance  "taraxigen."  Anaphylactic  shock  would  be  the 
result  of  a  sort  of  tautometric  intramolecular  rearrangement 
of  certain  very  labile  substances  contained  in  the  blood. 

Fundamentally  it  is  evident  that  all  these  different  ideas 
are  only  plays  on  words.  There  has  been,  and  is,  much 
discussion  in  current  chemical  literature  on  the  subject  of 
the  different  phenomena  and  processes  surrounding  immun- 
ity and  anaphylaxis  just  as  our  fathers  and  grandfathers 
discussed  symptoms,  pathogenicity  and  evolution  of  infec- 
tious diseases  before  the  discovery  of  bacteria,  and  in  order 
to  explain  these  things  there  has  been  created  a  complicated 
and  barbarous  terminology  which  has  incidentally  the  great 

^  Anaphylatoxin  and  Anaphylaxis,  Jour.  Am.  Med.  Assn.,  May  26,  1917. 


90  IMMUNITY  AND  ANAPHYLAXIS 

inconvenience  of  giving  grand  illusions  with  a  precision  which 
does  not  exist. 

Confusion  and  misunderstandings  result  in  the  vast 
majority  of  cases  from  the  forced  use  of  inaccurate  terms 
which  are  necessary  in  order  to  visualize  reactions  between 
substances  of  which  only  a  few  biological  properties  are 
known. 

And  the  differences  which  we  have  desired  to  establish 
in  the  nature  of  the  reactions  of  anaphylactic  shock  and 
of  chronic  anaphylaxis  (Arthus  phenomenon)  between  the 
guinea-pig,  rabbit,  goat,  horse  or  rat,  and  even  between 
French  and  American  guinea-pigs  could  arise  only  from 
the  fact  that  up  to  the  present  we  have  had  only  a  general 
idea  of  the  interpretation  of  various  observed  phenomena, 
clinical  or  experimental. 

But  although  the  words,  "anaphylaxis,"  "taraxis," 
"apo-  or  anaphylatoxins"  or  "taraxins"  are  not  important, 
the  distinctive  characters  of  shock  as  well  as  of  crises  of 
longer  duration  and  other  delayed  reactions  of  a  different 
nature  are  defined  as  much  by  the  pathogenicity  as  by  the 
symptoms. 

To  define  a  phenomenon,  it  is  not  sufficient  to  indicate 
the  process  by  which  it  is  produced:  We  ought  to  know  of 
what  it  consists;  in  other  words,  its  symptoms,  the  methods 
by  which  these  symptoms  are  produced  and  particularly  the 
properties  of  the  elements  which  combine  to  produce  them. 

But  if  we  do  not  know  all  the  properties  of  all  the  anti- 
gens and  of  all  the  antibodies  as  of  all  their  compounds,  we 
can  know  with  certainty  that  the  anaphylactic  state  can  be 
produced  only  by  antigens  which  form  with  their  antibodies 
insoluble  compounds.  We  have  seen  that  there  is  no  ana- 
phylaxis for  toxins  which  form  with  their  antitoxins  soluble 
compounds,  and  that  there  is  always  anaphylaxis  for  albu- 
mins, bacteria  and  their  broth  cultures  which  provoke  the 
formation  of  precipitates. 

The  most  convenient  theory  which  could  best  explain  the 
total  of  actually  known  facts  would  show  that  the  anaphy- 
lactic crisis  is  a  brisk  reaction  of  coagulation  caused  by  the 
union  in  the  organism  of  a  certain  dose  of  antigen  with  a 


ANAPHYLAXIS  91 

certain  dose  of  antibody,  no  matter  whether  the  antibody 
preexisted  normally  in  the  organism  or  whether  it  was  formed 
as  si  result  of  special  treatment.  In  the  case  of  tr,ue  antigens 
these  latter  are  coagulated  or  precipitated  by  the  antibodies 
of  the  organism.  In  the  case  of  non-antigenic  substances 
such  as  iodoform,  antipyrin,  peptones,  etc.,  it  is  the  injected 
substance  which  causes  the  coagulation  of  some  substance 
of  the  organism ;  in  either  case  the  nature  of  the  reaction  will 
be  always  the  same,  and  although  the  last  case  does  not 
come  within  the  limits  of  this  study,  it  is  not  without 
interest  to  note  it  in  order  to  avoid  confusions  and  possible 
misunderstandings. 

The  effects  of  these  coagulating  reactions  will  be  differ- 
ent according  as  the  precipitate  is  formed  exclusively  in  the 
blood  or  both  in  the  blood  and  in  a  certain  number  of  cells 
or  even  exclusively  in  the  cells.  If  formed  in  the  cells,  the 
effects  will  depend  upon  the  importance  of  the  intracellular 
antibody  in  the  life  of  the  cell  as  well  as  the  importance  of 
the  role  of  the  cell  in  the  life  of  the  organism. 

It  would  be  superfluous  to  dwell  here  upon  the  symptoma- 
tology of  anaphylaxis  in  its  different  degrees  or  its  different 
localizations  as  this  is  found  today  in  all  the  text-books  of 
pathology;  but  it  is  important  to  note  that  the  total  of 
symptoms  which  characterizes  anaphylactic  shock  includes: 

1.  The  action  of  the  recently  formed  poison— a  word  in 
incorrect  but  current  use  (Richet,  Vaughan,  Wheeler,  Fried- 
berger  and  others). 

2.  A  chemical  reaction  (combination  of  antigen  with 
antibody). 

3.  A  physical  or  absorption  reaction  (Mutermilch) . 

4.  A  mechanical  action  of  the  precipitate:  embolism, 
infarcts. 

5.  The  function  of  time  or  the  duration  of  reaction 
(Besredka) . 

6.  The  intervention  of  leukocytes  in  the  transformation 
and  transportation  of  precipitates  to  the  hemopoietic  organs. 

7.  Finally  dominating  the  mechanism  as  well  as  the  effects 
of  all  these  reactions  the  influence  of  the  central  nervous 
system. 


92  IMMUNITY  AND  ANAPHYLAXIS 

According  to  the  point  of  view  of  the  experimenter  it  is 
now  one,  now  another  of  these  agents  which  predominates 
in  his  mind  and  determines  his  preferences  for  this  or  that 
interpretation  of  the  effect.  Each  of  these  theories  contains 
a  part  of  the  truth  but  not  the  whole  truth,  and  it  is  there- 
fore necessary  that  the  apparent  effects  of  the  reaction  should 
be  considered  separately  without  attempting  to  understand 
their  basis  and  their  intricate  mechanism. 

But  we  have  seen  that  only  antigens  can  give  rise  to  the 
anaphylactic  state  in  the  organism.  We  have  seen  that  all 
antigens  are  colloids;  that  only  colloids  are  antigens,  that  in 
consequence,  the  nature  of  the  formation  of  antibody  should 
be  sought  in  the  colloidal  state  of  antigens,  or  in  other  words, 
by  seeking  to  understand  the  physicochemical  and  the  bio- 
logic properties  of  colloids  and  b}^  studying  the  transforma- 
tion which  heterologous  and  homologous  colloids  undergo 
in  the  interior  of  the  organism,  that  we  will  learn  to  know: 

1.  Why  colloids  cause  the  formation  of  antibodies. 

2.  Why  and  under  what  conditions  colloids  form  with  anti- 
bodies soluble  or  insoluble  compounds. 

3.  Why  the  compounds  of  antigens  with  their  antibodies 
are  harmless  when  they  are  soluble  and  pathogenic  when 
they  are  insoluble  and  why  this  should  necessarily  be  so. 

COLLOIDS. 

We  know  that  colloids  are  substances  which  do  not  crys- 
tallize and  which  therefore  cannot  be  isolated  from  their 
medium  in  pure  state  and  we  know  that  in  attempting  to 
purify  a  colloid  we  generally  cause  it  to  cease  to  be  a  colloid. 
According  to  the  "happy  simile  of  E.  Duclaux,  ''When  we 
try  to  analyze  an  albumin  by  chemical  methods,  we  act  as 
if  we  were  analyzing  a  watch  enclosed  in  a  case.  We  would 
find  iron,  copper,  silver,  gold  and  the  elements  which  com- 
pose glass  but  we  would  never  conclude  from  this  analysis 
that  these  elements  arranged  in  a  certain  way  and  put  in 
motion  in  a  certain  state  of  equilibrium  would  constitute 
a  total  which  would  enable  us  to  measure  time.  One  would 
admit  that  after  analyzing  a  watch  in  this  way,  by  grind- 


COLLOIDS  93 

ing  it  in  a  mortar  to  facilitate  the  action  of  strong  acids 
or  by  melting  it  at  a  temperature  of  about  1000°,  one  would 
destroy  not  only  the  instrument  which  tells  time  but  also 
those  landmarks  which  might  permit  us  to  identify  the 
individual  role  of  each  of  them  in  the  function  of  the  whole; 
that  is,  in  the  movement  of  the  hands." 

But  since  then  we  have  learned  to  do  better.'  By  sub- 
mitting an  albumin  to  an  action  less  brutal  than  that,  for 
example,  of  gastro-intestinal  digestion,  we  may  break  it 
down  little  by  little  without  destroying  the  entire  complexes 
—  "the  wheels"— which  compose  it,  and  by  continuing  in 
this  way  through  a  series  of  successive  disintegrations,  we 
would  find  that  every  albumin  which  is  a  colloid  is  at  last 
split  to  amino-acids  which  are  crystalloids.  We  know  that 
the  molecules  of  a  salt  in  solution  coalesce  one  with  another  to 
form  crystals  when  there  is  not  enough  solvent  to  keep  them 
a  certain  distance  apart,  but  we  do  not  know  how  and  why 
amines,  which  can  exist  as  free  molecules,  and  which  then 
obey  the  laws  of  salt  solutions  may  congregate  into  such 
complex  elements  as  colloids. 

It  would  be  especially  interesting  to  know  by  what  physi- 
cal or  chemical  agent  (electricity,  magnetism,  affinity)  these 
molecules  of  amino-acids  are  bound  and  held  together.  We 
will  know  this  certainly  some  time.  At  the  moment  we 
must  confine  our  study  to  the  biologic  and  physicochemical 
properties  of  the  albumin  as  we  find  it  in  its  complex  medium 
and  to  the  substances  which  result  from  its  successive  dis- 
integrations. Although  incomplete,  this  study  already  gives 
us  a  series  of  interesting  reflections  which  are  sufficiently 
exact  for  our  purpose;  to  learn  how  and  why  an  organism  can 
become  diseased,  and  perhaps  also  how  it  can  recover  under 
the  best  conditions. 

We  have  then  determined  that  of  all  the  products  of  the 
disintegration  of  an  albumin,  those  only  are  antigens  which 
are  still  in  the  colloidal  state. 

Free  amino-acids  are  no  longer  antigens.  There  is  here  a 
confirmation  of  the  fact  which  we  have  noted  above,  that 
only  colloids  can  be  antigens  and  it  is  possible  to  conclude 
from  this  that  foreign  albumins  taken  as  a  food  which  gastro- 


94  IMMUNITY  AND  ANAPHYLAXIS 

intestinal  digestion  is  incapable  of  splitting,  that  is  to  say, 
of  transforming  into  amino-acids  and  which  may  pass  into 
the  interior  of  the  organism  as  colloids  will  provoke  the 
formation  of  antibodies  and  in  consequence  the  anaphylactic 
state.  These  are  the  causes  of  the  habitual  or  accidental 
anaphylactic  intolerance  for  certain  foods,  as  well  as  for 
infections  by  mouth,  individual  or  specific,  in  typhoid, 
cholera,  tuberculosis,  etc. 

The  organism  can  nourish  itself  on  foreign  albumins  only 
in  cases  it  can  assimilate  them,  that  is  to  say,  can  transform 
them  into  albumins  of  its  own  species;  and  we  know  that 
to  do  this  it  can  absorb  them  only  in  the  completely  dis- 
integrated state  of  the  amino-acid.  This  disintegration  is 
the  role  of  gastro-intestinal  digestion.  What  then  becomes 
of  the  incompletely  digested  albumins  which  have  penetrated 
into  the  interior  of  the  organism  in  the  colloidal  state? 
They  can  neither  be  assimilated  nor  eliminated  in  the 
colloidal  state. 

Two  hypotheses  are  possible:  Either  they  would  accu- 
mulate in  some  part  to  which  would  be  brought  every  other 
unassimilable  foreign  body  where  they  would  be  surrounded 
by  leukocytes;  or  else  the  interior  of  the  organism  would 
finish  the  incomplete  gastro-intestinal  digestion  and  would 
render  them  assimilable  or  eliminable  as  amino-acids.  It 
is  this  last  hypothesis  which  happens  in  all  the  known  cases. 
It  is  true  that  up  to  the  present  we  have  never  been  able  to 
prove  this  parenteral  digestion,  but  if  we  have  no  direct 
experimental  proof  of  it,  we  know  with  certainty  by  numer- 
ous experiments  (Hamburger  and  Moro  and  others)  that 
when  we  inject  a  rabbit  with  horse  serum,  we  can  recover 
this  serum  in  the  rabbit's  blood  some  time  after  the  injection 
but  that  finally  this  serum  will  disappear  at  a  given  moment 
and  that  this  disappearance,  often  quite  sudden,  will  always 
coincide  with  the  appearance  in  the  rabbit's  blood  of  specific 
antibodies.  From  the  point  of  view  of  the  reaction  which 
follows,  it  is  of  little  importance  by  what  route  (intestinal, 
subcutaneous,  intravenous)  the  colloidal  antigen  penetrates 
into  the  organism. 

The  transformation  in  the  organism  of  a  colloid  into  a 


COLLOIDS  95 

salt  can  be  followed  at  the  present  time  with  some  precision 
only  for  a  colloid  obtained  by  synthesis  which  quite  recent 
researches  permit  us  to  consider  as  an  antigen.  This  syn- 
thetic colloid  is  disodo-dioxy-diamino-arsenobenzene-anti- 
monious-silver-bromide  (or  product  102). 

Judging  by  the  experiments  and  analyses  of  Mile.  Mitchel 
this  product  injected  into  the  blood  of  rabbits  as  a  colloid 
is  entirely  eliminated  by  the  kidneys  and  the  intestines  as 
a  salt.  We,  therefore,  say  that  the  colloid  has  undergone  in 
the  organism  a  transformation  commonly  called  digestion 
and  since  this  colloid  possesses  all  the  biologic  and  physico- 
chemical  properties  common  to  an  antigen,  since  it  gives 
in  the  organism  the  same  series  of  reactions  under  the  same 
conditions,  we  may  assume  by  comparison,  that  all  other 
antigens  undergo  in  the  organism  transformations  of  the 
same  nature;  that  introduced  as  colloids  they  will  be  digested, 
and  transformed  into  salts  and  as  such  either  assimilated 
or  eliminated. 

In  consequence  by  taking  a  purely  biologic  point  of  view, 
and  by  using  all  the  experimental  material  known,  we  must 
admit  that  the  injection  into  the  interior  of  the  organism  of 
a  colloid  antigen  which  is  digestible  will  always  produce  a 
reaction  of  digestion  on  the  part  of  the  organism  quite  as 
the  introduction  of  an  albumin  into  the  digestive  apparatus. 
And  we  may  add  with  some  certainty  that  the  formation  of 
antibody  in  excess  which  appears  in  the  blood  at  the  end  of 
the  incubation  period  can  be  only  the  result  of  the  normal 
reaction  common  to  every  living  cell  which  will  always  try 
as  long  as  it  lives  to  reproduce  and  multiply  a  substance  of 
which  it  has  need  or  which  it  loses  by  a  neutralizing  com- 
bination with  a  foreign  substance. 

We  may  thus  represent  the  steps  of  this  process  in  the 
following  simple  way: 

Every  organism  possesses  for  every  normally  digestible 
albumin  a  certain  normal  affinity  (and  this  is  not  surpris- 
ing since  every  albumin  is  constructed  on  the  same  plan 
and  belongs  to  the  same  chemical  family)  or,  in  other  words, 
a  certain  dose  of  normal  affinity  for  a  certain  dose  of  foreign 
albumin. 


96  IMMUNITY  AND  ANAPHYLAXIS 

If  the  dose  of  albumin  injected  is  strictly  equivalent  or 
less  than  the  dose  of  normal  affinity  every  antigen  injected 
will  be  fixed  by  normal  antibody,  digested,  assimilated  or 
eliminated  and  the  organism  will  reproduce  and  multiply 
this  normal  affinity-antibody  which  then  will  become  the 
antibody  in  excess.  If  the  injected  dose  of  albumin  is 
greater  than  the  dose  of  normal  affinity  the  antigen  will  fix 
itself  to  the  normal  antibody  en  surcharge  and  the  organism 
will  suffer  or  rather  the  antigen  in  excess  will  circulate  in 
the  blood  up  to  the  time  when  the  organism  can  produce  a 
quantity  of  antibody  sufficient  to  fix  and  digest  this  excess 
of  antigen.  It  is  only  after  a  total  disappearance  of  antigen 
that  the  antibody  in  excess  will  appear. 

In  this  way  is  explained  quite  easily  a  fact  which  until 
now  has  seemed  inexplicable.  We  know  that  if  a  small 
injection  of  antigen  causes  an  excess  of  antibody  and  the 
anaphylactic  state  to  appear  in  ten  to  fifteen  days,  the  injec- 
tion of  a  large  quantity  of  the  same  antigen  into  an  animal 
of  the  same  species  will  produce  the  same  effect  only  after 
an  incubation  period  of  some  weeks  or  even  months  simply 
because  the  existence  of  an  excess  of  antigen  in  the  circula- 
tion excludes  the  possibility  of  the  simultaneous  existence 
of  an  excess  of  antibody  in  the  organism. 

More  recently,  however,  Longcope  and  Rackemann^  have 
been  able  to  demonstrate  that  in  the  serum  disease,  which  as 
originally  shown  by  Von  Pirquet  and  Schick^  often  follows 
the  injection  of  antitoxic  or  antibacterial  serum  in  man, 
there  may  be  a  coexistence  of  antigen  and  antibody  in  the 
circulation. 

Working  with  cases  of  pneumonia,  which  had  been  treated 
with  antipneumococcus  serum  obtained  from  horses,  they 
found  that  the  horse  serum  persisted  unchanged  in  the  blood 
for  several  days,  and  that  in  a  few  cases  circulating  antibody 
could  be  demonstrated  in  the  same  specimen  of  patient's 
blood  serum  in  which  horse  serum  could  also  be  demon- 


.    1  The    Relation    of    Circulating    Antibodies    to    Serum    Disease,    Jour. 
Exp.  Med.,  1918,  xxvii,  341. 

2  Die  Serumkrankheit,  Leipsic  and  Vienna,  1915. 


COLLOIDS  97 

strated.  They  found  that  "the  rapid  diminution  of  antigen 
follows  the  rapid  rise  of  precipitin  and  is  coincident  with 
recovery  from  serum  disease";  so  that  although  the  two 
reagents  can  coexist,  they  cannot  both  be  "in  excess." 

Under  what  conditions  then  is  an  organism  sensitive  to 
anaphylaxis?  There  will  be  a  surcharge  of  antibodies. 
That  is,  all  the  cells  which  possess  a  special  affinity  for  the 
injected  antigen  will  have  multiplied  a  substance  which 
fixes  the  antigen,  holding  a  certain  quantity  en  surcharge 
and  allowing  the  remainder  to  pass  into  the  blood.  There 
will  thus  be  an  excess  of  antibody  in  the  cells  and  in  the 
blood.  If  at  this  time  we  inject  a  sufficient  quantity  of  the 
same  antigen  there  will  be  produced  a  reaction  of  the  same 
nature  as  the  first  time  but  the  effects  of  this  reaction  on 
the  organism  will  be  different,  because  the  quantities  and 
the  proportions  of  the  two  products  will  be  no  longer  the 
same  and  because  the  reaction  will  take  place  not  only  in 
the  cells  but  also  in  the  blood. 

We  have  seen  above  that  the  compounds  of  the  antigen 
with  their  antibodies  may  be  soluble  and  under  these  condi- 
tions they  are  neutral  for  the  organism  (diphtheria,  tetanus) 
or  else  they  form  coagula  or  precipitates,  and  are  pathogenic. 
Whenever  there  are  antibodies  in  excess  both  in  the  blood 
and  in  the  cells,  there  will  be  pathogenic  reactions  intra- 
vascular and  intracellular. 

The  reactions  will  be  pathogenic  not  because  there  is 
formed  on  the  second  injection  a  toxic  body  different  from 
that  which  is  formed  at  the  first  injection,  but  only  because 
this  new  body  will  form  much  more  rapidly  and  in  much 
larger  quantities  than  the  first  time.  Precipitates  formed 
in  the  blood  will  result  in  emboli,  infarcts,  etc.,  from  which 
apoplectic  attacks,  syncope,  abdominal  congestion,  pulmon- 
ary and  cutaneous  edema  accompanied  by  fall  of  tempera- 
ture and  intracellular  lesions  will  be  expressed  by  a  variety 
of  symptoms,  all  the  more  severe  as  the  cells  in  question  play 
a  more  important  role  in  the  general  economy.  These  last 
reactions,  especially  when  they  concern  the  nervous  cells 
to  a  greater  or  less  degree,  are  accompanied  by  fever.  Let 
us  note  in  passing  that  intravascular  reactions  when  they 
7 


98  IMMUNITY  AND  ANAPHYLAXIS 

are  not  rapidly  fatal  will  always  be  less  dangerous  than 
intracellular  reactions. 

We  may  thus  affirvi  that  the  basis  for  the  production  of  anti- 
body in  excess  is  the  obligation  to  digest  colloids  under  which 
the  organism  finds  itself  in  order  to  assimilate  or  eliminate 
these  colloids.  We  know  that  this  digestion  will  produce 
pathologic  manifestations  when  the  compound  of  antigen 
with  antibody  causes  a  precipitate:  but  on  the  contrary 
when  this  compound  is  soluble,  this  digestion  is  completely 
harmless. 

This  difference  in  the  intimate  mechanism  of  the  reactions 
which  together  result,  on  the  one  hand,  in  the  formation  of 
a  coagulum  or  of  a  precipitate  and,  on  the  other  hand,  of  a 
product  which  is  soluble  remains  to  be  explained. 

For  this  explanation  only  a  very  limited  amount  of  experi- 
mental material  is  at  hand.  The  basis  of  the  reply  is  the 
physicochemical  constitution  of  colloids  which  is  still  little 
understood.  Let  us  also  see  what  we  know  and  what  con- 
clusion we  can  draw  from  the  point  of  view  which  is  presented 
to  us. 

From  the  physical  point  of  mew  a  colloid  can  be  represented 
as  formed  by  granules  or  * 'micelles"  ^  composed  of  a  variable 
number  of  molecules  of  a  single  or  of  several  different  sub- 
stances. The  structure  of  these  "micelles"  is  unknown, 
but  we  may  assume  that  when  they  are  in  suspension  in  a 
liquid,  they  have,  because  of  surface  tension,  a  spherical  or 
ovoid  form.  The  volume  of  the  granules  of  the  simplest 
and  most  homogeneous  and  antigenic  colloid  which  we  know, 
arsenobenzene,  is  variable  not  only  because  the  "micelles" 
may  contain  a  larger  or  smaller  number  of  molecules  but 
because  several  "micelles"  may  be  combined  into  a  single 
granule.  Experiments  show,  moreover,  that  in  every  liquid 
containing  a  colloid  in  suspension  there  is  also  a  certain 
number  of  free  molecules.  Thus,  when  we  allow  a  solution 
of  luargol  (1  to  400)  in  0.5  to  0.7  per  cent,  salt  solution,  to 

^  The  word  "micelle"  is  used  to  define  the  units  of  albuminoid  matter 
of  every  colloid  in  the  same  sense  that  the  word  "molecule"  expresses  the 
unit  of  chemical  compounds.  The  word  "particle"  is  used  by  many 
American  authors  in  the  same  sense. 


COLLOIDS  99 

stand,  we  find  at  the  end  of  twenty-four  hours  that  there  is 
formed  in  the  liquid  which  was  first  uniformly  colored  and 
uniformly  fluid,  four  layers  distinctly  superimposed  one 
above  the  other.  At  the  top  is  a  layer  of  clear,  highly 
colored  fluid;  below  this,  two  layers  darker  and  more  turbid 
and  at  the  bottom  a  translucent  flocculent  precipitate.  At 
the  end  of  two  or  three  days  there  will  be  in  the  tube  only 
a  sediment  and  a  perfectly  transparent  slightly  colored 
liquid.  This  liquid  will,  even  when  saturated  with  salt,  be 
no  longer  turbid  and  will  traverse  dialyzing  membranes. 
There  is  thus  no  more  colloid  and  the  hianner  in  which  the 
precipitate  is  formed  and  digested  in  the  remainder  of  the 
original  fluid  shows  that  there  were  in  this  fluid  granules 
of  different  sizes. 

In  a  solution  exactly  disodic  there  will  be  at  the  end  of 
twenty-four  hours  about  50  per  cent,  of  the  product  in  the 
precipitate  and  respectively  25,  20  and  5  per  cent,  in  the 
layers  above  it. 

The  proportions  of  amino-acids  as  free  molecules  or 
grouped  into  more  or  less  voluminous  granules  may  be 
different  for  different  colloids  and  for  the  same  colloids 
according  to  the  conditions  of  the  medium  in  which  they 
occur.  But  if  we  judge  by  the  total  of  reactions  between 
colloids  and  cells  and  by  the  results  obtained  in  submitting 
colloids  to  dialysis,  we  can  see  that  in  serum  as  in  egg-white 
or  in  a  bacterial  albumin,  or  in  a  toxin,  that  these  fluids  con- 
tain granules  of  very  different  volumes  as  well  as  amino- 
acid  existing  as  free  molecules,  quite  as  has  been  established 
for  the  arsenobenzenes. 

Thus  in  recognizing  that  there  are  very  distinct  differences 
between  the  formation  of  a  crystal  in  which  the  molecules 
of  salt  are  mechanically  deposited  one  on  the  other  and  a 
colloidal  granule  in  which  the  molecules  are  very  probably 
bound  together  by  a  single  affinity  we  must  note  that  there 
are  no  clear-cut  distinctions  between  the  two  sorts  of  sub- 
stances when  considered  from  the  point  of  view  of  their 
physical  property  of  crossing  dialyzing  membranes. 

There  is  no  membrane  which  cannot  be  traversed  by  the 
smallest  granules  of  > every  .cpUojd  ^ijd^it;is  very  important 


100  IMMUNITY  AND  ANAPHYLAXIS 

to  appreciate  this  because  it  is  the  smallest  granules  of 
antigens,  which,  by  traversing  the  membranes  of  cells, 
provoke  the  condition  of  congestion  and  dilatation  of  the 
cellular  membrane  which  then  becomes  permeable  for  more 
voluminous  granules. 

From  the  chemical  point  of  view,  we  know  that  each  mole- 
cule of  the  chlorhydrate  of  dioxydiamino-arsenobenzene  may 
theoretically  combine  with  two  molecules  of  silver  chloride 
but  when  a  dilute  solution  of  silver  chloride  in  potassium 
cyanide  is  added  drop  by  drop  to  a  dilute  solution  (1  to  500) 
of  arsenobenzene,  we  find  that  each  drop  of  silver  chloride  is 
precipitated  en  masse  without  forming  a  globule  and  is  then 
redissolved.  If  the  liquid  is  carefully  shaken,  the  dissolu- 
tion of  each  drop  which  follows  becomes  more  difficult. 
When  we  reach  the  proportion  of  almost  one  molecule  of 
silver  chloride  to  one  molecule  of  arsenobenzene,  dissolution 
no  longer  takes  place. 

An  insoluble  precipitate  is  also  obtained  by  adding  quickly 
one  molecule  of  a  concentrated  solution  of  silver  cyanide  to 
twenty  molecules  of  arsenobenzene,  although  there  is  still 
in  the  liquid  enough  of  the  latter  to  fix  and  hold  in  solution 
nineteen  other  molecules  of  silver  cyanide.  The  difference 
in  these  two  cases  may  be  explained  by  assuming  that  in  the 
first  case  by  adding  slowly  into  dilute  media  and  by  shaking 
the  mixture  th^  silver  chloride  is  more  or  less  uniformly 
distributed  among  all  the  molecules  of  arsenobenzene  while 
in  the  latter  case  each  molecule  of  arsenobenzene  which 
comes  into  contact  with  silver  chloride  fixes  two  molecules 
of  it  and  there  is  thus  formed  an  insoluble  compound. 

The  granule  of  arsenobenzene  may  thus  fix  a  salt  for  which 
it  has  a  certain  affinity  in  quantity  equal  to  the  sums  of 
the  affinities  of  the  molecules  which  compose  it,  but  it  is 
evident  that  it  can  also  fix  less  of  them  and  it  is  thus  that 
we  can  explain  the  "phenomenon  of  surcharge'^  and  the 
"phenomenon  of  least  saturation"  already  described,  in 
studying  the  properties  of  mixtures  with  their  antibodies 
in  vitro  and  in  vivo. 

For  the  arsenobenzenes  we  know  exactly  the  chemical 
equivalents;  ^pr  b^ojogic  antigeas  we  do;nct;  kiiow  them  but 


COLLOIDS  101 

the  similarity,  and  even  the  identity  of  all  the  reactions  of 
arsenobenzenes  with  those  of  all  the  other  antigens,  allows 
us  to  assume  that  the  physicochemical  constitutions  are 
also  identical.  This  phenomenon  of  least  saturation  will 
explain  the  formation  of  toxons,  toxoids,  epitoxons,  epi- 
toxoids    in   mixtures    of   toxins  and   antitoxins    (Ehrlich). 

For  phenomena  of  absorption  and  hydrolysis,  the  precipi- 
tant action  of  neutral  salts  and  the  dissolving  action  of 
acid  or  alkaline  media  which  characterize  every  colloid 
permit  us  to  consider  each  colloidal  granule  as  a  sort  of  cell 
which  can  be  hydrated  and  inflated,  dehydrated  and 
retracted,  which  can  absorb,  retain  and  secrete  all  sorts  of 
salts  by  the  purely  physical  phenomenon  of  osmosis  with- 
out regard  to  chemical  combinations  which  can  affect  its 
amino  groups  and  other  molecules  by  their  special  affinities. 

The  nature  of  the  reactions  between  colloids  or  between 
colloids  and  salts  as  well  as  the  quantity  of  the  substances 
which  can  be  combined  or  absorbed  are  determined  espe- 
cially by  the  physical  characteristics  of  the  colloid.  These 
include  the  form  and  volume  of  the  granules  which  compose 
the  colloid  as  well  as  the  proportion  of  the  different  sized 
granules.  So  long  as  "the  choice"  of  substances  with  which 
a  colloid  may  combine  and  the  nature  of  the  compounds  thus 
formed,  depends  eventually  on  chemical  affinities  of  the 
molecules  which  enter  into  the  composition  of  the  granules, 
it  is  very  possible  to  imagine,  that  in  a  granule  composed, 
for  example  of  one  hundred  molecules,  ten  or  twenty  or  sixty 
of  these  molecules  will  form  new  combinations  while  the 
others  will  remain  intact.  According  to  the  proportion 
of  different  granules  the  physicochemical  properties  as  well 
as  biologic  effects  of  the  colloid  will  be  different. 

Arsenobenzene  is  the  simplest  colloid-antigen  which  we 
know;  its  granules  are  of  different  and  variable  size  but  all 
are  composed  of  molecules  of  the  same  amine.  Biologic 
antigens  in  general  have  a  much  more  complex  composition; 
casein,  for  example,  is  composed  of  a  dozen  different  amino- 
acids  (alanin,  leucin,  serin,  glutamic  acid,  aspartic  acid, 
arginin,  lysin,  hystidin,  cystin,  tyrosin,  phenylalanin, 
tryptophan)    and   it  is   certain   that   between   casein   and 


102  IMMUNITY  AND  ANAPHYLAXIS 

arsenobenzene  we  can  find  all  intermediary  substances.  It 
would  thus  be  very  interesting  to  know  whether  all  the 
different  amino-acids  which  are  found  in  casein,  in  serum, 
or  in  bacterial  antigens  are  united  in  different  proportions 
in  each  granule  or  whether  each  of  them  forms  different 
granules.  Biologic  chemistry  will  probably  undertake  some 
day  to  solve  these  problems  which  we  cannoL  take  up  now. 
What  appears  certain  is  that  all  the  colloids  of  egg-white  or 
of  serum  or  of  bacterial  bodies  when  introduced  into  the 
interior  of  the  organism  do  not  become  antigenic,  nor  do 
all  the  colloidal  granules  of  heterologous  origin  take  part 
in  the  same  degree  in  the  formation  of  specific  antibodies. 
Levaditi  and  Mutermilch^  have  shown  by  their  studies  on 
the  production  of  anti-nagana  antibodies  in  the  guinea-pig, 
rabbit  and  rat  on  the  one  hand  and  in  the  hen  on  the  other 
hand,  that  antibodies  produced  by  the  same  antigens  in 
animals  of  different  species  are  not  identical. 

Different  antibodies  can  be  produced  only  by  different 
antigens,  which  means  that  in  the  particular  case  brought 
forward  by  Levaditi  and  Mutermilch,  products  of  bacterio- 
lysis of  the  trypanosome  do  not  form  a  uniform  antigen 
but  these  products  contain  a  mixture  of  colloidal  granules 
whose  composition  and  affinities  are  different.  In  con- 
sequence the  colloidal  granules  w^hich  are  antigenic  for  the 
organism  of  the  rabbit,  guinea-pig  and  rat  on  the  one  hand 
and  of  the  hen  on  the  other  hand  are  not  compounds  of  the 
same  amino-acids  or  at  least  are  not  grouped  in  the  same 
way.  We  have  also  seen  that  in  the  case  of  Bacillus  typhi 
murium  the  substance  virulent  for  mice  is  not  the  same 
which  gives  this  bacteria  its  virulence  for  rats.  These  two 
examples  allow  us  to  conclude  that  in  complex  colloids  formed 
of  every  sort  of  amino-acid  these  latter  are  not  uniformly 
distributed  among  all  the  granules  but  constitute  groups  of 
granules  of  different  chemical  compositions. 

And  if  this  is  so,  we  should  necessarily  conclude  that  every 
colloidal  granule  of  an  albumin  or  of  a  complex  colloid  which 
is  not  antigenic  ought  to  be  immediately  digested  and  trans- 

1  Antibody  and  Animal  Species,  Ann.  de  I'lnst.  Pasteur,  1913,  xxvii,  924. 


COLLOIDS  103 

formed  to  crystalloids  in  a  way  different  from  antigenic 
colloids.  This  allows  us  to  approach  the  question  of  the 
digestion  of  homologous  albumin,  which  with  the  exception 
or  crystallin  (the  substance  of  the  lens)  can  be  assimilated 
without  producing  the  formation  of  an  antibody  and  without 
ever  giving  rise  to  a  state  of  anaphylactic  intolerance. 

But  how  can  we  represent  this  assimilation  of  homologous 
albumin?  It  is  impossible  to  imagine  an  unbroken  albumin 
penetrating  into  a  cell.  Consequently  a  homologous  albu- 
min must  be  transformed  into  free  amino-acids  just  like  a 
heterologous  albumin;  only  this  transformation  must  operate 
in  another  way. 

By  studying  this,  after  what  we  know,  it  seems  as  if  a 
homologous  albumin  was  directly  transformed  into  free 
amino-acids  in  the  blood  and  fluids  in  the  organism  without 
passing  through  the  stage  of  coagulation  or,  in  other  words, 
as  if  there  were  in  each  organism  a  substance  capable  of 
destroying  or  of  binding  the  ties  by  which  amino-acids  are 
united  in  granules  and  of  thus  freeing  them  and  making  them 
assimilable.  The  example  of  the  transformation  of  a  col- 
loidal arsenobenzene  into  "  novo-arsenobenzene"  which  is  a 
salt  by  the  fixation  of  formaldehyde  sulphoxalate  of  sodium 
to  the  amino  group  of  dioxydiamino-arsenobenzene  permits 
us  to  assume  that  this  is  the  case. 

It  is  thus  very  probable  that  the  colloids  of  foreign  albu- 
mins which  are  not  antigens  are  transformed  to  crystalloids 
in  the  same  way  as  homologous  albumins.  This  is  not  sur- 
prising when  we  think,  as  already  indicated,  of  the  original 
unity  of  every  animal  species  and  of  the  similarity  of  the 
elementary  composition  of  all  albumins,  which  differ  among 
themselves  much  more  by  the  proportions  than  by  the 
qualities  of  the  chemical  parts  which  compose  them.  What 
should  differ  especially  are  the  ties  by  which  the  molecules 
are  bound  together  into  colloidal  granules.  Whatever  are 
the  differences  of  detail  between  different  albumins  and  the 
colloids  which  compose  them,  the  total  of  our  knowledge 
of  the  digestion  of  non-antigenic  and  antigenic  colloids  in 
the  interior  of  the  organism  permits  us  to  visualize  the 
mechanism  of  these  two  sorts  of  processes  in  the  following 


104  IMMUNITY  AND  ANAPHYLAXIS 

way:  Every  organism  possesses  in  its  fluids  certain  sub- 
stances (normal  antibodies)  in  a  sufficient  quantity  to 
rapidly  transform  by  a  single  operation  any  quantity  of 
non-antigenic  colloids  into  crystalloid  solutions  which  can 
be  assimilated  or  eliminated  and  by  the  same  procedure 
which  permits  it  to  digest  these  in  its  own  tissues. 

Every  organism  can  produce,  as  a  result  of  a  suitable 
preparation,  a  specific  antibody  by  which  every  antigenic 
colloid  can  be  transformed  into  a  crystalloid  but  here  the 
process  of  this  transformation  may  take  place  in  one  of 
two  different  ways,  either  as  a  single  reaction  in  the  case  of 
non-antigenic  colloids  (toxins,  antitoxins)  or  by  two  suc- 
cessive reactions,  of  which  the  first  consists  of  the  formation 
of  a  coagulum  and  the  second  of  the  dissolution  of  this 
coagulum  (all  the  other  albumins  and  colloidal  foreign 
antigens) . 

From  what  we  know  of  the  transformation  of  the  arseno- 
benzenes,  we  may  assume  that  in  the  case  of  non-antigenic 
colloids  as  in  the  case  of  toxins,  the  antibody,  whether  normal 
or  in  excess,  acts  especially  upon  the  ties  which  bind  the 
amines  into  colloidal  granules  to  neutralize  these  ties.  In 
the  case  of  antigenic  colloids  the  antibody  in  excess  forms 
first  new  combinations  with  the  molecules  of  these  antigens 
by  rearranging  the  granules  among  themselves  and  thus 
causing  the  formation  of  precipitates  or  coagula  which  ren- 
der the  subsequent  liberation  of  molecules  slower  and  more 
difficult. 

ANTIBODY. 

It  remains  for  us  to  investigate  the  physicochemical 
nature  of  antibodies  and  we  must  recognize  that  this  is  the 
least  known  element  of  the  problem.  We  know  that  the 
production  of  antibody  in  excess  is  the  result  of  a  vital 
reaction  of  the  cell  because  even  if  a  dead  cell  or  a  dead  tissue 
could  fix  a  certain  quantity  of  antigen  in  the  same  way  and 
by  the  same  affinity  as  living  tissue  it  would  be  impossible 
for  it  to  reproduce  and  multiply  this  fixation  substance 
which  in  the  living  organism  becomes  the  antibody  in  excess. 
This  explains  why  the  production  of  antibody  is  necessarily 


ANTIBODY  105 

always  inversely  proportional  to  the  pathogenic  action  of 
antigens. 

We  know  that  the  substance  to  which  the  role  of  normal 
antibody  belongs  can  fulfil  different  functions  which  are 
more  or  less  important  in  the  normal  life  of  the  cell.  This 
"substance"  may  be  in  an  organ  of  sense  or  a  function  of 
nutrition  or  of  reproduction  or  finally  a  substance  of  reserve 
and  in  each  the  immunizing  excitation  or  the  lesion  will 
be  manifested  by  its  different  effects  on  the  function  of 
the  particular  tissue  and  on  the  general  economy.  We  know, 
further,  that  it  is  not  always  the  same  cells  of  an  organism 
which  are  sensitive  to  the  action  of  an  antigen.  Where,  for 
example,  it  is  the  cells  of  the  central  nervous  system  which 
are  exclusively  or  more  particularly  sensitive  to  the  action 
of  an  antigen,  the  production  of  antibody  is  very  precarious 
if  not  absent,  probably  because  the  nerve  cells  do  not  recup- 
erate and  because  the  excitation  even  of  this  tissue,  however 
slight,  always  results  in  profound  disturbances  of  the  general 
economy.  We  may  conclude  that  the  less  important  the 
role  of  the  particular  tissue,  the  easier  and  less  harmful  will 
be  the  process  of  immunization.  This  is  almost  all  that 
we  can  say  as  to  the  biologic  origin  of  antibodies. 

As  to  their  physicochemical  nature,  we  know  that  anti- 
bodies are  one  of  those  components  of  "antiserum"  which  it 
has  been  quite  impossible  to  isolate  by  dialysis.  We  assume, 
at  least  tentatively,  that  they  are  colloids,  but  we  cannot 
prove  it  directly.  The  example  of  the  transformation  of 
coagulated  arsenobenzene  when  one  adds  to  the  molecules 
an  acid  or  base  which  holds  the  colloidal  granules  in  suspen- 
sion in  water;  the  redissolution  of  the  coagulum  as  well  as 
the  dislocation  of  the  colloidal  granules  by  a  sort  of  sulpho- 
nation  will  serve  to  prove  that  antibodies  may  be  something 
much  more  simple  than  a  colloid,  but  if  this  is  possible  for 
arsenobenzene  it  seems  today  too  simple  for  antibodies  and 
all  the  other  antigens.  Let  us  be  content  for  the  moment 
to  remember  the  essential  simplicity  of  the  reactions  which 
determine  the  transformations  of  arsenobenzenes  and  to 
hope  that  later  researches  will  help  us  to  recognize  the 
nature  and  the  mechanism  of  biologic  antigens. 


106  IMMUNITY  AND  ANAPHYLAXIS 

Summary.— 1.  Salts  introduced  into  the  interior  of  an 
organism  may  be  assimilated  or  eliminated  without  under- 
going any  transformation  because  they  can  cross  dialyzing 
membranes. 

2.  Colloids  cannot  be  assimilated  or  eliminated  under  the 
same  conditions  because  they  cannot  cross  dialyzing  mem- 
branes. 

3.  Gastro-intestinal  digestion  results  in  the  transforma- 
tion of  specific-colloid-albumins  into  salts  (amino-acids) 
which  are  no  longer  specific  and  with  which  the  organism 
reconstructs  the  albumins  of  its  species. 

4.  When,  as  a  result  of  incomplete  intestinal  digestion 
an  albumin  penetrates  into  the  interior  of  the  organism  it  is 
this  interior  which  must  achieve  digestion  and  this  doctrine 
applies  to  all  albumins  or  colloids  introduced  into  the  interior 
either  subcutaneously,  intravascularly  or  through  the 
intestines. 

5.  Cells,  tissues  and  organs  of  the  interior  of  the  organism 
are  adapted  only  in  a  certain  measure  to  this  function  of 
digestion  and  in  a  given  time  can  transform  only  a  certain 
quantity  of  albumin  or  of  foreign  colloids.  Each  time  that 
a  cell  fixes  a  quantity  of  a  substance  to  be  digested  in  excess 
of  what  it  can  easily  digest  (phenomenon  of  surcharge), 
there  will  be  intracellular  indigestion  which  disturbs  the 
vital  functions  and  the  physiologic  state  of  the  cell  for  the 
reason  that  there  is  no  method  for  the  evacuation  of  the 
undigested  surplus.  This  is  the  case  for  toxins,  ricin,  abrin, 
venins  and  certain  sera  which  are  directly  toxic  for  some 
tissues. 

6.  Intracellular  digestion  can  be  explained  only  by  an 
attraction  and  fixation  of  the  substance  to  be  digested  by  a 
substance  of  a  cell;  or  by  a  chemical  affinity  between  these 
two  substances,  which  results  in  the  formation  of  a  new 
compound.  When  this  operation  is  not  pathogenic  for  the 
cell  the  cell  reproduces  and  multiples  what  it  has  lost  in 
the  combination;  in  this  way  we  may  represent  the  forma- 
tion of  antibody  in  excess. 

7.  The  presence  in  the  organism  of  antibody  in  excess  in 
the  cells  and  in  the  blood,  which  can  of  itself  produce  certain 


ANTIBODY 


107 


functional  disturbances  (tuberculosis),  increases  the  diges- 
tive capacity  of  the  organism  for  the  corresp>onding  antigen, 
but  at  the  time  renders  the  digestion  more  rapid  and  more 
tumultuous  and  one  of  two  different  processes  may  then 
take  place: 

In  the  first,  digestion  takes  place  at  one  time  and  the 
antigen,  transformed  to  an  assimilable  or  eliminable  product, 
becomes  completely  neutral  to  the  organism.  The  antibody- 
antigen  compound  produces  no  disturbances  at  all:  diph- 
theria, tetanus,  non-antigenic  colloids. 

In  the  second,  digestion  takes  place  in  two  successive 
phases:  first,  coagulation  and  second,  dissolution  of  the 
coagulum.  Here  the  sudden  formation  of  the  coagulum  will 
produce  immediate  or  delayed  pathologic  manifestations 
whenever  the  quantity  of  antigen  is  greater  than  the  capacity 
for  the  rapid  dissolution  of  the  coagulum:  septicemia  and 
heterologous  albumins. 

8.  All  the  pathologic  symptoms  caused  by  an  antigen  which 
are  manifested  in  the  organism  at  the  time  when  it  contains 
corresponding  antibody  in  excess  are  anaphylactic  in  nature. 
A  crisis  of  anaphylaxis  is  nothing  but  a  crisis  of  indigestion. 
The  disturbances  are  produced  by  a  sudden  rupture  of  the 
normal  equilibrium  between  the  state  of  gel  and  the  state  of 
sol  of  those  colloids  which  enter  into  the  composition  of  cells 
and  blood. 

The  severity  of  the  disturbance  produced  by  these  reactions 
is  determined  by : 

(a)  The  quantities  and  relative  proportions  of  the  reacting 
substances. 

(b)  The  concentration  of  these  substances  and  in  conse- 
quence the  duration  of  the  reaction. 

(c)  The  intracellular  and  intravascular  localization  of 
lesions. 

(d)  The  secondary  and  often  delayed  effect  of  these  lesions 
on  the  general  economy. 

In  the  spontaneous  infectious  diseases,  intravascular  reac- 
tions are  always  less  dangerous  than  intracellular  reactions 
because  these  latter  often  result  in  the  destruction  of  cells  and 
consequently  in  lesions  of  the  tissues  which  are  severe  and 


108  IMMUNITY  AND  ANAPHYLAXIS 

persistent.     In  contrast  with  intracellular  reactions,  intra- 
vascular reactions  may  be  considered  as  therapeutic. 

9.  The  necessity  or  the  production  of  antibody  in  excess 
results  from  the  obligation  under  which  the  organism  finds 
itself  to  transform  antigenic  colloids,  which  have  penetrated 
by  any  way  whatever  into  its  blood  and  tissues,  into  salts. 

10.  The  mechanism  of  this  digestion  is  still  unknown  but 
we  may  suppose  following  the  example  of  the  transformations 
of  arsenobenzenes,  that  in  certain  cases  (toxins)  the  antibody 
is  a  substance  which  binds  the  ties  which  unite  the  amines 
in  colloidal  granules  and  thus  transforms  the  colloid  into  a  salt 
neutral  for  the  organism;  and  that  in  every  case  there  is  first 
fixation  by  th^  molecules  of  a  colloidal  granule  of  a  substance 
which  unites  the  granules  to  each  other  to  form  a  coagulum 
or  a  precipitate  and  finally  there  is  another  substance  which 
dissolves  the  precipitate  and  destroys  the  ties  of  the  molecules. 

We  may  note  in  passing  that  the  same  substance  may 
coagulate  or  dissolve  according  to  the  proportions  of  the 
reacting  substances.    Thus  in  two  words: 

The  pathologic  state  in  infectious  diseases  is  due  to 
anaphylaxis. 

Anaphylaxis  is  an  indigestion  which  may  be  intracellular 
or  intravascular  or  both. 

This  indigestion  consists  in  the  inability  of  the  organ  to 
rapidly  transform  colloidal  antigens  into  salts. 

When  it  is  intravascular,  the  disturbance  will  be  rapid  and 
immediate:  anaphylactic  shock;  when  it  is  intracellular  the 
disturbance  and  the  lesions  which  result  may  be  more  or  less 
delayed  and  will  last  for  hours,  days  or  dozens  of  years  (tuber- 
culosis, leprosy,  syphilis) :  chronic  anaphylaxis. 

From  the  point  of  view  of  the  evolution  of  infectious  diseases, 
anaphylaxis  ought  to  be  considered  as  a  pathologic  reaction  of 
the  process  of  immunity. 


CHAPTER   VI. 

THE  INFLUENCE  OF  THE  CENTRAL  NERVOUS 

SYSTEM  ON  IMMUNIZING  REACTIONS 

AND  ON  ANAPHYLAXIS. 


The  influence  of  the  central  nervous  system  on  the  pro- 
cesses of  immunity  and  anaphylaxis  is  not  at  the  present 
time  understood,  at  least  from  the  biochemical  point  of  view. 
It  is  indisputable  that  the  cells  of  an  organism,  even  the 
leukocytes,  have  no  individual  independent  life,  concur  in 
all  their  functions  to  make  a  perfectly  coordinated  whole. 
In  other  words,  that  the  specific  functions  of  each  tissue, 
organ,  gland  and  cell  are  strictly  dependent,  not  only  on 
the  physicochemical  affinities  of  the  substances  which  com- 
pose them,  but  also  and  especially  on  the  action  and  condition 
of  the  central  and  sympathetic  nervous  system,  and  on  its 
conscious  and  subconscious  reactions. 

Syncopies,  respiratory  and  gastro-intestinal  disturbances 
produced  by  emotions,  whether  spiritual  or  psychic,  real  or 
suggested,  which  simulate  so  accurately  the  syndrome  of 
anaphylactic  shock  in  total  or  in  part,  the  chronic  disturb- 
ances of  general  nutrition  produced  by  grief;  the  activation 
of  salivary  or  gastric  secretion  by  the  sight  of  certain  foods— 
all  prove  that  the  nervous  system  can  produce  in  the  cells 
all  manner  of  reactions  without  the  direct  intervention  of 
any  foreign  product  whatever. 

Moreover  in  a  diarrhea  caused  by  a  violent  emotion  or 
in  an  urticaria  of  hysterical  origin  it  is  certainly  not  the 
direct  action  of  the  peripheral  nerves  which  can  in  a  few 
moments  liquefy  the  intestinal  contents  or  produce  edemas 
in  different  areas  of  the  skin.  These  reactions  in  the  last 
analysis  can  be  the  result  only  of  physicochemical  modifi- 
cations which  are  produced  in  the  interior  of  particular 


no    INFLUENCE  OF  CENTRAL  NERVOUS  SYSTEM 

cells.  We  know,  moreover,  nothing  of  the  exact  mechanism 
of  these  reactions  nor  of  the  substances  which  enter  into 
them  but  we  may  assume  that  there  is  a  disturbance  of 
that  metabolism  which  regulates  intracellular  nutrition  and 
causes  the  capillary  dilatation. 

What  is  certain,  and  what  is  important  to  remember,  is 
that  excitations  of  a  purely  psychic  order  which  involve 
those  highest  nerve  cells  which  determine  conscious  states 
may  result  in  functional  disturbances  of  certain  tissues  or 
organs,  that  is  to  say,  in  purely  physicochemical  reactions. 

We  do  not  know  with  any  certainty  whether  the  inverse 
is  often  true,  whether,  for  example,  it  is  possible  to  ward 
off  a  contagion  or  its  effects  by  a  particular  state  of  mind 
but  we  do  know  that  it  is  possible  to  mitigate  anaphylactic 
shock  by  certain  narcotics  as  shown  by  the  experiments  of 
Besredka  inspired  by  E.  Roux.  Besredka  noticed  that  the 
surest  method  of  producing  anaphylactic  shock  in  the 
guinea-pig  is  to  inject  the  antigen  into  the  brain.  At  that 
time  E.  Roux  suggested  to  him  the  idea  of  anesthetizing 
the  animal  before  the  second  injection.  The  result  was 
as  hoped  for;  animals  narcotized  by  alcohol,  ether,  ethyl 
chloride,  urethane  or  chloroform,  especially  by  the  first  two, 
were  rendered  insusceptible  to  anaphylactic  shock  while 
controls  succumbed  almost  alwaj^s  in  a  few  seconds  or  in 
a  few  minutes.  The  first  was  found  vaccinated  against  a 
later  injection  (anti-anaphylaxis) .  This  experiment  leads 
us  to  a  combination  of  very  complex  phenomena  which  it  is 
almost  impossible  to  interpret. 

The  effect  produced  by  an  antigen  on  a  hypersensitive 
organism  depends  to  a  certain  degree,  as  we  have  seen 
above,  quite  as  much  on  the  dose  of  the  antigen  injected 
as  on  the  rapidity  with  which  the  reactions  take  place. 
For  each  condition  of  hypersensitiveness  a  dose  of  antigen 
can  be  determined  which  will  produce  no  apparent  trouble, 
a  dose  which  will  vaccinate  and  a  dose  which  will  kill. 
However,  no  dose  is  always  constant  in  its  effect.  A  dose 
which  will  produce  violent  death  in  an  animal  when  quickly 
injected  within  a  few  seconds,  will  become  protective  if 
the  injection  is  allowed  to  last  a  few  minutes.    The  effect 


INFLUENCE  OF  CENTRAL  NERVOUS  SYSTEM    111 

thus  depends  upon  the  time  during  which  the  intracellular 
reactions  are  allowed  to  take  place  and  anesthesia  has  no 
other  role  than  to  prolong  the  duration  of  the  reactions. 
By  anesthetizing  the  nerve  cells  the  transmission  of  the 
excitation  to  the  nerve  centers  and  to  the  particular  tissues 
is  impeded. 

The  combination  between  antigen  and  antibody  in  excess 
takes  place  in  spite  of  narcosis,  because  the  animal  is  vac- 
cinated by  the  dose,  but  the  pathologic  effect  of  the  reaction 
between  the  two  substances  is  lessened  either  because  the 
duration  of  the  reaction  is  longer,  or  better,  because  the 
hypersensitiveness  of  important  nerve  cells  has  prevented 
organs  of  tissues  from  reacting  pathologically.  We  can 
explain  this  better  by  a  somewhat  exaggerated  comparison: 

When  a  stone  engages  in  a  gall-duct  or  in  the  urethra  the 
walls  of  the  canal  contract  as  if  they  were  trying  to  hinder 
the  passage  of  the  foreign  body.  Local  or  general  anesthesia 
will  prevent  the  contraction  (and  the  pain  at  the  same  time) 
so  that  if  the  dimensions  of  the  stone  do  not  exceed  the 
capacity  for  expansion  of  the  canal,  the  stone  will  continue 
on  its  way  without  pathologic  manifestations. 

Experiences  have  shown  that  certain  nervous  excitations 
may  produce  pathologic  manifestations,  analogous  to  those 
which  characterize  anaphylactic  shock,  and  that  anesthesia 
of  the  nerve  centers  may  hinder  these  manifestations  by 
moderating  the  resulting  reactions  and  especially  by  hinder- 
ing the  secondary  reaction  of  the  organism.' 

We  know  only  two  sorts  of  nervous  influences  but  it  is 
very  probable  that  there  are  many  others  and  that  their 
effects  may  be  different,  either  good  or  bad  for  the  organism. 
We  suspect,  for  example,  that  when  in  an  infectious  disease 
(typhoid  fever,  pneumonia,  tuberculosis,  etc.)  nervous  symp- 
toms are  predominant,  the  process  of  immunization  does 
not  take  place  or  takes  place  incompletely  and  the  prognosis 
is,  therefore,  always  grave.  We  also  know  that  in  antitoxic 
immunization,  the  production  of  antibodies  is  all  the  more 
rapid  and  abundant  when  the  nervous  sensibility  of  the 
treated  animal  is  better  protected  against  intoxication. 

Thus,  the  guinea-pig  is  much  more  easily  immunized  against 


112    INFLUENCE  OF  CENTRAL  NERVOUS  SYSTEM 

diphtheria  toxin  than  the  rabbit  because  in  the  guinea-pig 
the  non-fatal  dose  of  this  toxin  is  completely  fixed  and 
retained  by  the  cellular  tissue  and  never  produces  nervous 
crises;  in  the  rabbit  the  same  toxin  is  not  retained  by  cellu- 
lar tissue  and  always  paralyzes.  But  in  attempting  to 
immunize  these  two  animals  against  tetanus  toxin  the 
reactions  and  results  are  exactly  reversed.  It  is  thus  very 
probable  that  in  these  two  cases  the  production  of  anti- 
bodies is,  in  a  certain  measure,  modified  by  the  influence  of 
the  central  nervous  system. 

We  may  quote  here  the  experiences  of  KendalP  on  the 
action  in  vitro  of  suprarenal  cortex  on  ammonium  carbo- 
nate. This  action  is  very  different  according  to  whether 
the  operation  for  the  removal  of  the  cortex  is  done  in  an 
animal  normally  sluggish  without  having  undergone  any 
nervous  excitement  or  whether  in  an  animal  recently  and 
violently  frightened.  In  the  first  case  the  ammonium  car- 
bonate undergoes  no  modification;  in  the  second,  it  is  trans- 
formed into  a  poorly  defined  substance  which  Kendall  has 
called  pre-urea  because  when  excreted  in  urine  it  is  trans- 
formed into  urea. 

The  researches  of  Cannon^  demonstrate  beautifully  the 
actual  physiological  changes  brought  about  by  the  central 
nervous  system.  Cannon  showed  that  after  any  violent 
emotion,  such  as  fear  or  rage,  there  is  a  marked  liberation 
of  "epinephrin"  from  the  suprarenal  cortex  and  a  liberation 
of  glycogen  from  the  liver.  This  sudden  liberation  of  epi- 
nephrin,  which  takes  place  in  a  matter  of  seconds,  causes 
in  turn  the  production  of  many  and  varied  disturbances  in 
the  organism  such  as  stimulation  of  the  sympathetic  nerves, 
increase  in  the  blood  coagulability  and  in  the  relative  pro- 
portion of  red  blood  cells. 

Psychic  excitations  can  thus  produce  a  proved  modifica- 
tion in  metabolism  and  resulting  from  this  a  change  not 
only  in  the  substances  contained  in  the  suprarenal  cortex 
but  in  the  quantities  of  substances  secreted. 

1  Experimental  Hyperthyroidism,  Jour.  Am.  Med.  Assn.,  1917,  Ixix,  610. 

2  Am.  Jour.  Physiol.,    1915-16,  vols,  xl-xlii. 


INFLUENCE  OF  CENTRAL  NERVOUS  SYSTEM     113 

Summary.— If  the  facts  actually  known  hardly  permit 
us  to  understand  the  nature  and  the  mechanism  of  the 
influences  which  different  varieties  of  excitations  of  nerve 
centers  exert  on  the  reactions  between  antigens  and  anti- 
bodies we  may  assume  that  these  reactions  are  probably 
never  purely  local,  that  they  are  always  influenced  by 
nervous  states,  conscious  or  subconscious,  direct  or  reflex. 
The  suggestion  which  we  may  draw  from  this  is  to  investi- 
gate the  action  of  different  anesthetics,  hypnotics  and 
narcotics  or  infections,  especially  in  the  severe  cases  with 
nervous  disturbances. 


CHAPTER  VII. 
THERAPEUTIC  MEASURES. 

In  the  evolution  of  pathologic  states  caused  by  actually 
known  antigens  it  is  necessary  to  distinguish  between  a  latent 
state  of  anaphylaxis  and  an  actual  state  of  anaphylaxis. 

By  latent  anaphylaxis  we  mean  that  the  organism  is 
surcharged  with  antibodies  in  excess  as  a  result  of  the  pre- 
vious injections  or  ingestion  of  the  antigen  or  as  a  result  of 
the  periods  of  remission  of  those  diseases  with  relapses  and 
with  long  and  slow  evolution  such  as  tuberculosis,  syphilis, 
trypanosomiasis  and  malaria.  Each  time  that  a  sufficient 
quantity  of  antigen  in  fresh  doses  is  joined  with  these  anti- 
bodies in  excess  more  or  less  violent  crises  will  occur. 

By  actual  anaphylaxis,  we  mean  that  the  organism  shows 
symptoms  of  disease  in  which  a  state  of  anaphylactic  crisis 
is  maintained  on  the  one  hand  by  the  presence  of  new  quan- 
tities of  antigens  due  to  the  multiplication  of  bacteria  and 
on  the  other  hand  by  the  continued  formation  of  antibodies 
on  the  part  of  the  organism  so  that  antibodies  will  always 
be  in  excess.  The  formation  of  momentarily  insoluble  com- 
pounds of  antigens  and  antibody  constitutes  the  pathologic 
state  of  chronic  anaphylactic  crises. 

We  know  that  we  can  abort  a  crisis  or  an  anaphylactic 
shock  by  anti-anaphylactic  vaccination.  According  to 
Besredka  and  Steinhardt  and  according  to  Al.  Wright,  cases 
of  definite  anaphylaxis  can  often  be  treated  successfully  by 
an  identical  method— bacteriotherapy,  that  is  to  say,  by 
injections  of  small  doses  of  antigen— the  cause  of  the  disease. 

From  the  work  of  Besredka  we  know  that  preventive 
vaccination  is  rigorously  specific  and  for  bacteriotherapy  we 
seek  likewise  to  obtain  curative  preparations  made  with  a 
culture  of  the  bacterial  species  which  is  the  cause  of  the 
infection  or  with  the  actual  germs  in  the  infection,  "auto" 
vaccines. 


THERAPEUTIC  MEASURES  115 

In  both  instances,  the  preventive  and  curative  action  can 
be  explained  by  a  progressive  neutraUzation  of  the  antibody 
in  excess  which  results  in  making  the  organism  return  to  the 
normal  state  following  a  new  injection  of  the  same  antigen 
and  in  the  two  cases  "prophylaxis"  or  therapy  confers  very 
rapidly  on  the  organism  a  temporary  anti-anaphylactic 
immunity,  but  a  new  dose  of  the  antibody  will  establish  the 
preceding  anaphylactic  condition  even  more  acutely. 

The  anti-anaphylactic  vaccination  of  Besredka  as  well  as 
the  bacteriotherapy  of  Wright  are  discoveries  due  to  one  of 
those  happy  chances  in  the  course  of  experiments  which  have 
revealed  to  the  experimenters  facts  which  they  did  not  seek 
but  which,  from  the  practical  point  of  view,  have  shown  them- 
selves to  be  more  important  than  those  which  they  did  seek. 

And  it  is  interesting  to  realize  that  this  principle  of  anti- 
anaphjdactic  vaccination  should  arise  from  the  false  idea 
that  antitoxic  vaccination  should  lead  to  an  anti-anaphy- 
lactic analogous  to  antitoxin  (Roseneau,  Anderson,  Otto) 
quite  in  the  same  way  as  bacteriotherapy  (or  vaccine 
therapy)  arose  in  the  mind  of  Wright  from  anti-infectious 
vaccination  (anti-anthrax  vaccination,  and  the  treatment  of 
rabies:  Pasteur,  Roux,  Chamberland) .  Nobody  has  sought 
to  establish  any  relation  whatever  between  those  two  phe- 
nomena. 

Besredka  was  far  from  doubting  when  an  anaphylactic 
shock  was  aborted  by  his  successive  injections,  that  he 
obtained  the  same  results  by  reactions  identical  to  those  of 
Wright  with  his  vaccine  therapy,  but  if  Besredka  reached 
little  by  little  an  exact  conception  or  at  least  the  only  prob- 
able conception  of  the  mechanism  of  anti-anaphylactic 
vaccination,  the  explanation  of  the  facts  of  bacteriotherapy 
is  still  and  w^ill  always  be  an  "article  of  faith,"  or  a  "religion" 
for  all  those  who  pretend  to  see  in  the  pathologic  manifesta- 
tions of  an  infectious  disease  the  effects  of  a  poison  and 
nothing  else  and  in  the  recovery  an  "antitoxic  virtue"  of  a 
drug  or  serum. 

Moreover  close  inspection  will  reveal  that  the  mechanism 
of  vaccination  and  of  the  treatment  of  anaphylaxis  is  simple 
and  easy  of  explanation  only  when  previous  vaccinating  or 


116  THERAPEUTIC  MEASURES 

curative  antigens  are  specific  or  homologous  (autogenous 
vaccines).  The  mechanism  is  singularly  complicated  when 
it  is  attempted  to  associate  the  identical  results  obtained  by 
non-specific  antigens  especially  by  the  skeptophylaxis  of 
Ancel  and  Bouin  or  by  the  tachyphylaxis  of  Gley  and 
Champy,  with  lymphotherapy  from  the  preventive  point 
of  view  or  with  chemotherapy  from  the  curative  point  of 
view.  In  skepto-  or  tachyphylaxis,  whose  discovery  in  1880^ 
may  be  considered  chronologically,  as  the  origin  of  all  the 
researches  on  anaphylaxis  and  bacteriotherapy,  the  crises 
»of  anaphylaxis  can  be  aborted  by  a  vaccination  injection  of 
any  antigen  whatever  (Roger  and  Josue  Lambert,  Ancel  and 
Bouin). 

In  proteosotherapy,  Rumpf  used  injections  of  sterilized 
cultures  of  pyocyaneus  with  success  in  typhoid  fever  (1893); 
Hallopeau  and  Roger  cultures  of  streptococci  and  of  prodi- 
giosus  in  tuberculous  lupus  (1896)  and  quite  recently  Ch. 
Nicolle,  James  W.  Jobling  and  his  numerous  collaborators. 
Bull,  Dunklin,  Eggstein,  Manier,  Peterson,  and  others, 
have  obtained  undoubted  results  in  treating  acute  and 
chronic  rheumatoid  arthritis  of  unknown  origin  by  different 
proteoses,  peptones  or  bacterial  bodies. 

In  lymphoserotherapy  (Baillon,  Artaud,  de  Vevey,  etc.) 
as  well  as  in  chemotherapy,  it  is  quite  impossible  to  imagine 
the  direct  action  of  the  particular  antigen  on  the  antibody  in 
excess  as  in  proteosotherapy. 

From  this  is  the  conclusion  that  either  the  mechanism  of 
anti-anaphylactic  vaccination  and  that  of  specific  bacterio- 
therapy are  different  from  those  of  tachyphylaxis,  of  proteoso- 
and  of  chemotherapy;  or  else  the  explanation  which  we  have 
just  given  is  inexact  or  more  or  less  incomplete. 

The  experimental  material  at  our  actual  disposal  does  not 
permit  us  to  answer  this  question  in  a  sufficiently  exact  way. 
What  we  can  say  with  certainty  is  that  if  the  effects  obtained 

1  A.  Schmidt  Mulheim  has  shown  that  a  non-pathogenic  dose  of  peptone 
rendered  an  animal  insusceptible  to  a  pathogenic  dose  injected  shortly  after 
the  first  (Beitrage  zur  Kentniss  des  Peptons,  etc.,  Arch.  f.  Physiol.,  1880). 

About  the  same  time,  Woolbridge  established  the  same  result  by  paren- 
teral injections  of  organ  extracts  and  Martin  (Australia)  by  parenteral 
injections  of  certain  venins. 


THERAPEUTIC  MEASURES  117 

by  vaccination  as,  for  example,  in  treatment  by  homolo- 
gous and  by  heterologous  antigens  are  in  certain  cases 
undoubted,  we  cannot  place  these  two  methods  in  the  same 
category.  Statistics  and  clinical  observations  as  an  index  of 
successful  treatment  must  be  relied  on  with  caution  since 
the  degrees  of  disease  vary  so  widely.  We  know  that  an 
elevation  of  temperature  of  3  or  4°  can  help  the  organism  to 
rid  itself  of  certain  bacteria  (gonococci)  by  aiding  the  disso- 
lution of  certain  precipitates  and  we  know  that  the  intro- 
duction of  any  antigen  whatever,  in  immunizing  doses,  pro- 
duces certain  abnormal  reactions  or  stimulates  those  which 
are  already  begun.  (Action  of  pilocarpine  in  the  production 
of  antitoxins  (Madsen  and  Salomonsen) .) 

It  is  always  the  specific  agents  which  exercise  the  most 
obvious  action  and  if  the  neutralization  of  antibody  in  excess 
plays  an  important  role  in  the  cure  of  anaphylactic  crises, 
this  role  is  only  concomitant  with  other  reactions  of  a  nature 
and  mechanism  little  understood.  We  do  not  know  whether 
in  skepto-  or  tachyphylaxis  and  in  proteosotherapy  all  the 
antigens  are  distinctly  interchangeable  or  whether  in  anti- 
anaphylactic  vaccination,  the  vaccinating  antigens  are  or 
should  always  be  as  rigorously  and  exclusively  specific  as  in 
experiments  with  egg-white. 

Friedberger  and  others  have  said  that  after  a  pathogenic 
injection  of  anaphylatoxin  the  serum  of  the  treated  animal 
contains  less  "complement"  than  it  contained  before  the 
injection  and  that  at  the  same  time  the  blood  becomes  inco- 
agulable as  in  tachyphylaxis.  It  is  then  very  probable  that 
in  certain  cases,  if  not  in  all,  that  the  neutralization  of  the 
excess  of  complement  may  be  equivalent  to  the  neutraliza- 
tion of  the  excess  of  antibody  rendered  inactive. 

A  vast  field  is  here  open  for  experiments  which  will  not 
fail  to  influence  the  therapy  of  the  future.  By  these  re- 
searches medicine  aAd  its  methods  will  be  sooner  rendered 
more  exact  and  comprehensive.  The  problems  to  be  solved 
will  always  be  infinitely  simplified  if  it  is  borne  in  mind  that 
all  the  phenomena  described  under  the  names  of  skepto- 
or  tachyphylaxis,  anaphylaxis,  anaphylactic  crisis,  anti- 
anaphylaxis,    bacterio-,    proteoso-,    lympho-,    and    chemo- 


118  THERAPEUTIC  MEASURES 

therapy  and  even  under  serum  therapy  whose  discovery  has 
arisen  in  different  ways  and  in  which  researches  have  devel- 
oped parallel  to  the  others,  but  without  touching,  are  all 
provoked  by  reactions  of  the  same  nature. 

In  fact,  the  products  which  provoke  skepto-  or  tachy- 
phylaxis are  no  other  than  the  anaphylatoxins  so  that  skepto- 
phylaxis  is  synonymous  with  anti-anaphylatoxic  vaccination. 
An  anaphylactic  crisis  is  produced  by  reactions  identical  to 
those  produced  by  anaphylatoxin  and  in  these  two  phe- 
nomena there  is  this  single  difference  that  in  the  first,  the 
organism  furnishes  the  reactive  substance  (antibody  in 
excess)  while  in  the  second,  the  antigen  furnishes  it.  A 
series  of  injections  of  a  disodic  arsenobenzene  will  render  the 
organism  anaphylactic  to  a  later  or  second  injection  of  the 
same  product.  The  serum  of  the  treated  organism  will 
become  more  precipitating  than  normal  serum:  Mono- 
sodium  arsenbenzene  is  an  anaphylatoxin  because  this 
product  on  injection  is  more  easily  precipitable  than  the 
disodic  compound. 

Finally  latent  anaphylactic  crisis  is  made  to  abort  exactly 
by  the  same  method  as  an  outspoken  anaphylactic  crisis  is 
cured.  The  confusion  of  facts  is  caused  only  by  a  lack  of 
understanding  of  the  background  on  which  each  develops 
and  to  coordinate  these  it  is  only  necessary  to  find  in  the 
experimental  material  at  hand  suggestions  useful  for  thera- 
peutics. 

CHEMOTHERAPY. 

Chemotherapy  may  w^ell  profit  by  all  the  experiments  dis- 
cussed above.  We  know  (Dalimier)  that  the  injection  of  a 
small  dose  of  a  disodic  arsenobenzene  can  protect  the  organ- 
ism from  the  pathologic  eft'ects  of  a  larger  dose  and  that  the 
pathologic  state  already  existing  and  caused  by  a  large  dose 
may  lead  to  recovery  or  rapid  improvement  by  a  mechanism 
identical  to  that  of  bacteriotherapy.  It  would  be  interesting 
to  see  whether  it  were  possible  to  cure  and  especially  to 
prevent  anaphylactic  or  anaphylatoxic  accidents  caused  by 
arsenobenzenes  by  using  other  antigens— for  example,  pep- 
tone, sera,  or  bacterial  bodies.    If  this  were  possible,  it  would 


CHEMOTHERAPY  119 

be  easy  to  increase  the  actual  dose  of  arsenobenzene.  On 
account  of  individual  intolerance  which  is  always  possible 
and  difficult  to  foretell,  it  is  not  safe  to  inject  at  once  a  strong 
dose  of  arsenobenzene,  but  by  proceeding  with  a  series  of 
small  injections  the  risk  of  habituating  a  parasite  as  well  as 
the  organism  to  the  drug  would  be  diminished.  There  is 
therefore  every  inducement  to  attempt  to  find  whether  by 
the  injection  of  vaccinating  doses  of  other  antigens,  the 
tolerance  of  the  organism  for  arsenobenzene  can  be  increased 
so  that  a  more  surely  curative  dose  of  this  drug  can  be  injected 
safely.  As  to  the  curative  or  parasiticidal  action  of  chenaical 
compounds,  we  can  say  with  certainty  that  since  they  kill 
infecting  bacteria  directly,  all  these  products  prevent  the 
anaphylactic  state  caused  by  bacteria  much  more  than  they 
themselves  cause  them. 

The  disappearance  from  the  lesions  and  from  the  blood  of 
treponema,  spirilla  or  trypanosomes  following  an  injection 
of  arsenobenzene  by  no  means  proves  that  the  product  has 
directly  poisoned  them.  Quite  frequently  the  same  result  is 
obtained  by  bacteriotherapy.  Cases  of  typhoid  fever  have 
been  cured  by  bacteriotherapy  in  twenty-four  hours  (Widal) 
or  forty-eight  hours  (Fournier)  and  here  it  is  impossible  to 
conceive  of  a  direct  destruction  of  living  bacteria  by  the 
injection  of  dead  bacteria. 

But  at  the  same  time  we  know : 

1 .  That  to  cure  a  case  of  recurrent  fever  or  to  make  trepo- 
nema disappear  from  chancres  in  twenty-four  hours  requires 
the  following  drug  doses : 

Novoarsenobenzene 0.45  gin. 

Arsenobenzene 0.25-0.30     " 

Luargol 0.10-0.15     " 

"Product  No.  219" 0.0^-0.05     " 

(This  last  is  a  product  of  luargol  in  which  the  silver  bromide 
is  partially  replaced  by  copper  bromide). 

Intramine  (of  MacDonagh) 1.00  gm. 

2.  That  in  the  different  experimental  trypanosomiases 
luargol  and  ''product  No.  219"  are  much  more  active  than 


120  THERAPEUTIC  MEASURES 

606  and  galyl  for  Trypanosoma  gambiense,  Rhodesiense  and 
Surra  but  they  are  less  active  for  nagana.  The  product 
No.  219  is  the  only  one  with  which  up  to  the  present  time  it 
is  possible  to  destroy  the  trypanosome  dimorphon  in  the 
blood  of  mice.  The  principle  is  probably  similar  to  that  of  an 
antitrypanosome  serum  which  causes  agglutination  of  the 
parasites. 

3.  In  infectious  lymphangitis,  galyl  (of  Mouneyrat)  is 
much  more  active  than  606  or  luargol. 

4.  In  bacterial  septicemias  (acute  and  chronic)  all  these 
products  are  of  equally  little  efficacy.  The  injection  of  606 
may  prevent  the  development  of  anthrax  when  injected  at 
the  same  time  or  very  shortly  after  the  virus,  but  luargol  in 
which  the  bromide  is  replaced  by  the  iodide  of  silver  is  much 
more  actiye  than  606,  probably  on  account  of  the  specific 
action  of  the  iodine.  A  prolonged  treatment  with  the  product 
219  has  brought  about  the  fairly  rapid  recovery  (two  to  three 
months)  of  several  severe  cases  of  generalized  glandular 
tuberculosis. 

The  conclusions  which  these  facts  suggest  are: 

1.  Although  the  action  of  every  arsenobenzene  is  equally 
anti-anaphylactic,  that  is  to  say,  causes  in  the  organism 
reactions  of  the  same  sort,  the  substances  of  the  organism 
and  the  substance  of  the  infecting  parasites  which  react  with 
the  drug  are  not  the  same  for  each  drug.  By  multiplying  the 
different  affinities  of  the  product  the  fixation  and  neutraliza- 
tion of  a  much  larger  nmnber  of  different  substances  of  the 
parasite  is  brought  about  and  thus  the  field  of  action  of  the 
product  is  extended  to  a  greater  number  of  parasites. 

For  example,  if  606  acts  only  by  the  free  aflSnities  of  its 
arsenic,  219  may  act  by  its  own  affinities  of  arsenic  and  in 
addition  by  those  of  antimony,  bromine,  silver  and  copper. 

2.  It  is  probably  not  necessary  to  complicate  the  composi- 
tion of  therapeutic  products  by  elements  with  great  anti- 
toxic or  antiseptic  power  as  these  might  in  the  long  run 
become  themselves  dangerous  for  the  tissues. 

It  is  true  that  certain  organic  compounds  (toxins,  venins, 
sera)  are  more  pathogenic  than  the  most  toxic  metallic  salts 
but  since  it  is  a  question  of  obtaining  anaphylactic  effects 


BACTERIOTHERAPY  AND  SERUM  THERAPY      121 

and  since  it  is  possible  to  attain  these  effects  without  using 
in  the  composition  of  drugs  any  toxic  metals,  the  idea  of 
MacDonagh  of  replacing  the  arsenic  of  arsenobenzene  by  a 
sulphate  or  iron  salt  deserves  to  be  given  serious  consideration. 

BACTERIOTHERAPY  AND  SERUM  THERAPY. 

As  long  as  it  is  possible  to  produce  antigens  and  antibodies 
by  synthesis,  bacterio-  and  serum  therapy  will  be  the  methods 
of  choice  in  the  treatment  of  infectious  diseases.  In  bacterio- 
therapy  the  uncertainty  in  the  dose  is  most  often  the  cause 
of  partial  failure  or  of  severe  accidents  which  have  made 
chnicians  hesitate  to  adopt  this  method  and  to  apply  it  to  all 
cases  where  practically  possible. 

But  experiments  in  anti-anaphylaxis  and  in  skepto-  and 
tachyphylaxis  permit  us  at  the  present  to  make  this  method 
more  sure  and  efficacious.  We  may  assume  that,  other 
things  being  equal,  specific  or  autogenous  bacteriotherapy 
will  always  give  us  the  best  and  most  constant  results;  but 
it  is  necessary  to  find  the  best  curative  preparation;  the  best 
method  of  its  administration  (whether  by  mouth,  by  rectum, 
subcutaneously  or  intravenously)  and  finally  the  best  dosage. 

Curative  preparations  may  be  either: 

1.  A  culture  on  a  gelatin  emulsion  in  saline  or  distilled 
water  killed  by  heat  (58°  to  100°  C.)  and  as  fresh  as  possible. 

2.  The  same  cultures  prepared  in  the  same  way  but  more 
or  less  autolized. 

3.  The  same  culture  killed  by  antiseptics. 

4.  A  living  culture  of  attenuated  virulence. 

5.  A  living  culture  of  attenuated  virulence  and  then 
sensitized. 

The  best  method  of  administering  curative  preparations  is 
always  by  intravenous  injection.  It  will  always  give  the 
quickest  results  and  will  not  aggravate  the  condition  of  the 
patient.  When  the  quantity  of  antigen  is  predetermined  (by 
determining  the  quantity  of  antibody  in  excess),  vaccines 
can  be  injected  without  danger. 

The  least  dangerous  method  is  to  give  the  vaccme  by 
mouth  but  it  is  evident  that  this  method  can  be  applied  with 


122  THEHAPEUTIC  MEASURES 

success  only  in  case  gastro-intestinal  digestion  is  incapable  of 
transforming  the  bacterial  albumins  into  their  amino-acids 
(typhoid,  cholera,  f urunculosis) . 

The  dose  should  be  regulated  according  to  the  quantity 
of  antibody  in  excess  contained  in  the  blood  of  the  patient. 
Too  large  a  dose  may  produce  a  rapidly  fatal  anaphylactic 
crisis:  too  small  a  dose  will  give  a  slight  or  inappreciate 
result.  As  it  is  often  difficult  to  rapidly  determine  the  exact 
quantity  of  antibody  in  the  blood  of  the  patient  one  may 
replace  a  single  injection  by  a  series  of  injections  made  under 
the  following  conditions : 

Supposing,  for  example,  that  the  total  quantity  of  bacteria 
to  be  injected  is  five  hundred  million,  there  would  be  given  by 
vein: 

First,  a  primary  injection  of  500,000  bacteria;  a  second 
injection,  ten  minutes  later  5,000,000  bacteria;  a  third  injec- 
tion, five  minutes  later  50,000,000  bacteria;  a  fourth  injection, 
three  to  five  minutes  later  450,000,000  bacteria;  by  exhaust- 
ing little  by  little  the  antibodies  in  excess,  one  could  more 
easily  reach  the  dose  of  antigen  necessary  to  neutralize  all 
the  antibody  without  provoking  a  pathologic  reaction. 

SERUM  THERAPY. 

It  is  evident  that  an  injection  of  antibacterial  serum,  that 
is  to  say,  of  an  antibody,  into  an  organism  containing  already 
an  excess  of  this  antibody  can  have  no  curative  effect  where 
the  disease  is  due  to  a  chronic  anaphylactic  state.  In  fact 
we  know  that  the  injection  of  such  a  serum  always  causes  a 
passive  anaphylactic  state  and  we  know  that  in  a  certain 
number  of  diseases,  tuberculosis,  plague,  typhoid,  strepto- 
coccus, antisera  have  given  up  to  the  present  time  no  appre- 
ciable result.  There  are,  moreover,  septicemic  diseases  such 
as  erysipelas,  anthrax,  pneumonia,  cerebrospinal  meningitis, 
in  which  the  action  of  specific  sera  is  indisputable.  Either 
the  bacteria  of  these  infections  secrete  in  the  organism  toxins 
analogous  to  those  of  diphtheria  and  tetanus  and  the  serum 
acts  in*this  case  by  its  antitoxic  properties;  or  else  the  action 
of  the  serum  is  analogous  to  that  of  a  proteose  or  of  a  non- 


SeHum  therapy  123 

specific  protein.  The  two  actions  may  furthermore  take 
place  simultaneously. 

Diphtheria  and  erysipelas  are  very  instructive  in  this  way. 
Most,  if  not  all,  horses  yield  in  the  normal  state  antidiph- 
theritic  and  antistreptococcus  serum  of  very  appreciable 
potency  (up  to  50  antitoxic  units  per  c.c.  for  diphtheria)  and 
although  it  is  unlikely  that  horses  which  are  naturally  refrac- 
tory for  these  two  diseases  could  acquire  this  spontaneous 
immunity,  it  is  possible  that  the  serum  of  normal  horses  acts 
like  a  non-specific  antigen  and  this  is  not  surprising  since  we 
know  that  carmin  will  neutralize  tetanus  toxin.  In  other 
words,  a  biologically  neutral  and  non-specific  substance  can 
produce  a  reaction  of  the  same  nature  as  a  specific  antitoxin. 
The  differences  are  only  in  proportions  and  degrees. 

It  would  not  be  difficult  to  elaborate  a  program  of  studies 
which  would  enable  us  to  exactly  diff'erentiate  the  cases  of 
intoxication,  due  to  the  direct  action  of  toxins,  from  cases  of 
anaphylaxis  caused  by  bacterial  albumins,  or  in  other  words, 
the  cases  amenable  to  treatment  by  antisera  from  those  in 
which  such  a  serum  could  do  only  harm. 


chapter  viii. 

principles  of  the  classification  of 
Infectious  diseases. 

In  every  infectious  disease,  the  pathologic  manifestations 
are  produced  by  the  action  of  antigens  on  tissues  and  organs 
and  the  differences  in  the  evolution  of  symptoms  of  these 
different  diseases  are  determined  by: 

1 .  The  physicochemical  composition  and  the  physiological 
properties  of  antigens  and  antibodies. 

2.  The  nature  of  the  compounds  formed  by  antigens  with 
their  normal  antibodies,  whether  soluble  or  insoluble,  neutral 
or  active. 

3.  The  elective  affinities  of  antigens  for  certain  tissues. 

4.  The  physiological  role  of  the  antibodies  in  the  life  of 
those  cells  which  fix  the  antigen. 

5.  The  role  of  the  fixing  cells  in  the  life  of  the  organism. 

6.  The  adaptation  of  the  infecting  bacteria  to  life  in  the 
infected  organism. 

7.  The  nature  of  the  complications  which  may  result  from 
the  lesions  produced. 

The  similarities  and  the  differences  in  the  physicochemical 
properties  of  antigen,  in  the  biologic  action  of  the  reacting 
substances,  in  the  nature  and  effects  of  the  reactions;  all 
serve  as  a  basis  for  a  natural  classification  of  infectious  dis- 
eases; but  it  is  evident  that  such  a  classification  will  only 
be  of  purely  theoretical  interest. 

Every  therapeutic  intervention  ought  to  be  based  on  the 
knowledge  of  the  facts  which  we  have  just  reviewed,  because 
they  are  facts  which  determine  successive  stages  in  the 
evolution  of  each  disease  caused  by  an  antigen.  A  classifica- 
tion permits  us  at  the  same  time  to  group  in  a  rational 
manner  therapeutic  methods   and   to   foretell   the  results 


CLASSIFICATION  OF  INFECTIOUS  DISEASES      125 

which  a  certain  preventive  or  curative  method  should  be 
capable  of  yielding  in  each  particular  case.  By  proceeding 
in  this  way,  we  ought  little  by  little  to  make  therapeutics  an 
exact  science. 

Thus,  for  example,  the  fact  that  in  diphtheria  the  antigen 
in  excess  forms  with  the  normal  antibody  a  pathogenic  com- 
pound while  the  antigen  with  antibody  in  excess  forms  a 
compound  which  is  neutral  for  the  organism,  permits  us  to 
conclude  that  preventive  or  curative  treatment  by  antitoxic 
serum  is  the  most  efficacious  method.  And  we  should  con- 
clude that  in  all  other  cases  when  reactions  between  anti- 
bodies and  antigens  are  of  the  same  nature  the  same  treat- 
ment will  yield  analogous  results.  On  the  other  hand  where 
the  antibody  in  excess  forms  with  the  antigen  an  insoluble 
compound  and  where  it  is  precisely  this  excess  of  antibody 
which  is  the  cause  of  the  pathologic  manifestations  (ana- 
phylactic state)  (as  in  typhoid  fever)  the  disease  cannot  be 
treated  by  injections  of  antibody,  which  already  exist  in 
excess  but,  on  the  contrary,  must  be  treated  by  anti-anaphyl- 
actic  methods— that  is,  by  injections  of  antigen  which  will 
neutralize  this  excess  of  antibody. 

There  are  diseases  in  which  the  antibody  in  excess  neutral- 
izes the  antigen  without  producing  appreciable  disturbances 
and  there  are  others  in  which  the  antibody  in  excess,  while 
neutralizing  the  antigen,  produces  by  its  combination  with 
the  latter  a  pathologic  reaction.  This  difference  between  the 
properties  of  the  compounds  of  antigens  with  their  antibodies 
in  excess  allows  us  to  divide  the  known  diseases  into  two 
great  groups.  Our  knowledge  of  the  properties  of  antibodies 
and  of  antigens  as  well  as  of  the  compounds  formed  by  these 
two  substances  is  altogether  too  incomplete  in  most  cases 
for  us  to  assign  at  the  present  their  exact  place  in  each  dis- 
ease. Judging  from  what  we  actually  know,  we  can  group 
together  on  the  one  hand,  diphtheria,  tetanus,  certain  pneu- 
monias, perhaps  anthrax  fever,  erysipelas,  and  certain  cere- 
brospinal meningitides  in  which  the  antigen  acts  directly  and 
rapidly  on  tissues  and  is  neutralized  by  the  antibody  in 
excess  without  anaphylaxis  and,  on  the  other  hand,  all  the 
other  septicemias  in  which   the  incubation  period  is  more 


126      CLASSIFICATION  OF  INFECTIOUS  DISEASES 

or  less  long  and  in  which  the  pathologic  manifestations  are 
anaphylactic  in  nature. 

The  characters  of  the  subgroups  and  species  will  be  deter- 
mined by  the  affinities  of  antigens  for  different  tissues  as 
well  as  by  the  nature  and  properties  of  antibodies  and  the 
role  of  these  latter  in  the  life  of  the  sensitive  cells.  Thus,  for 
example,  tuberculosis,  glanders  and  leprosy  on  the  one  hand; 
syphilis,  trypanosomiasis,  relapsing  fever  and  malaria  on  the 
other  hand  form  two  closely  allied  groups  of  diseases.  As 
common  characteristics  they  have  the  physicochemical 
properties  of  their  antigens  and  the  nature  of  their  anti- 
bodies. In  both  groups  immunity  and  anaphylaxis  persist 
only  as  long  as  the  infection  itself.  The  quantity  of  antibody 
produced  in  excess  is  relatively  very  small  and  the  sensitive 
cells  cease  to  produce  it  immediately  after  the  disappearance 
of  the  infecting  bacteria.  On  the  other  hand  the  bacteria 
seem  to  adapt  themselves  very  easily  to  the  medium  of  the 
infecting  organism  and  may  live  in  it  for  years  or  even  dozens 
of  years.  This  facility  of  adaptation  on  the  one  hand, 
determines  the  more  or  less  regular  cyclic  evolution  of  these 
diseases  whose  mechanism  has  been  the  object  of  the  very 
interesting  study  of  nagana  in  the  guinea-pig  by  Levaditi 
and  Mutermilch. 

Typhoid  and  paratyphoid  fever,  plague,  eruptive  fevers, 
yellow  fevers,  the  hemorrhagic  septicemia  in  animals,  bovine 
plague,  the  horse  sickness  of  South  Africa  form  another 
group  of  diseases  which  are  related  to  the  preceding  group 
by  the  physicochemical  properties  of  their  antigens  as  well 
as  by  the  pathogenic  properties  of  the  compounds  of  these 
antigens  with  antibodies  in  excess.  This  second  group 
differs  from  the  first  by  the  nature  and  origin  of  the  anti- 
bodies which  sensitive  cells  produce  in  relatively  large 
quantities  and  reproduce  for  a  long  time  after  recovery  from 
the  disease.  In  these  cases  acquired  immunity-anaphylaxis 
may  persist  for  several  years. 

Gonorrhea,  influenza,  aphthous  fever  form  still  another 
group  which  is  related  to  the  type  of  tuberculosis  by  the  intra- 
cellular origin  of  the  antibodies  which  determines  the  short 
duration  of  immunity-anaphylaxis  but  differs  from^it  by 


CLASSIFICATION  OF  INFECTIOUS  DISEASES      127 

the  nature  and  the  localization  of  the  sensitive  cells  and  in 
consequence  by  the  lesions  produced  especially  by  the 
rapidity  of  the  evolution  because  the  bacteria  of  these  dis- 
eases are  less  easily  adapted  to  the  infected  medium  than 
those  of  tuberculosis  or  of  syphilis. 

Summary,— From  the  point  of  view  of  their  evolution,  all 
infectious  diseases  have  as  a  common  characteristic  the 
formation  of  antibodies  in  excess  under  the  action  of  antigens. 

The  common  distinguishing  characteristic  between  the 
different  diseases  lies  in  the  physicochemical  nature  and  the 
biologic  properties  of  the  compounds  formed  by  the  action 
of  the  antibodies  in  excess  with  their  antigens.  These  com- 
pounds may  be  either  soluble  and  neutral  and  here  the 
immunizing  action  of  the  antigens  will  confer  on  the  organ- 
ism immunity  without  anaphylaxis  (diphtheria);  or  com- 
pounds may  be  insoluble  and  pathogenic  and  here  the  immun- 
izing action  of  the  antigen  confers  on  the  organism  immunity 
and  also  anaphylaxis  (almost  all  septicemias). 

The  two  great  families  of  infectious  diseases  can  be  sub- 
divided according  to  the  affinities  of  antigens,  the  relative 
quantity  of  antibodies  produced,  and  the  duration  after 
recovery  of  the  production  of  antibodies.  This  latter  prob- 
ably depends  upon  the  nature  and  upon  the  role  which  the 
mother  substance  of  the  antibody  fulfills  in  the  life  of  the 
cell. 

In  the  second  great  group  three  types  can  be  distinguished : 

1.  Tuberculosis. 

2.  Typhoid  fever. 

3.  Gonorrhea,  aphthous  fever,  and  a  subtype;  syphilis  and 
malaria. 

The  species  in  these  groups  may  be  differentiated  and 
characterized  by  the  affinities  of  antigens  for  different 
tissues,  by  the  nature  of  lesions  produced  and  by  the  adapta- 
tion of  bacteria  to  their  host. 


CHAPTER  IX. 
GENERAL  CONCLUSIONS. 

The  collection  of  studies  on  the  evolution  and  nature  of 
pathologic  states  which  we  have  just  analyzed,  especially 
the  phenomena  of  surcharge  or  of  least  saturation  which  are 
found  in  mixtures  of  antibodies  and  antigens;  the  recent 
researches  of  physiology,  more  particularly  those  of  Willcock 
and  Hopkins,^  and  of  Osborn  and  MendeP  on  the  importance 
of  certain  amino-acids  (tryptophane  and  lysin)  in  the  nutri- 
tion, growth  and  reproduction  of  higher  animals  as  well  as 
the  quite  recent  work  of  Van  Slyke.^  The  present  significance 
of  the  amino-acids  in  physiology  and  pathology  shows  that 
the  amino-acids  pass  from  the  intestines  into  the  blood  with- 
out undergoing  any  transformation  and  at  least  in  part  are 
absorbed  directly  by  the  tissues. 

These  researches  lead  us  to  consider  the  organism  from 
the  point  of  view  of  its  physicochemical  composition  as  a 
total  composed  of  colloidal  "micelles,"  formed  by  the  union  of 
a  larger  or  smaller  number  of  homo-  or  heterogeneous  amino- 
acids  held  together  by  certain  chemical  affinities.  By  reason 
of  surface  tension,  the  molecules  are  more  dense  at  the  peri- 
phery than  at  the  center  so  that  the  peripheral  layer  acts 
like  a  dialyzing  membrane. 

A  "micelle"  thus  constituted  can  fix  salts  by  chemical 
affinities  of  its  molecules  and  can  absorb  them  by  osmosis 
and  can  exchange  salts  as  well  as  water  with  the  exterior.  It 
can  also  by  the  same  affinities  fix  itself  to  other  units  and 
form  much  larger  voluminous  granules.  It  is  thus  not  the 
molecule  but  the  colloidal  "micelle"  which  is  the  chemically 

1  The  importance  of  Individual  Amino-acids  in  Metabolism,  Jour,  of 
Physiol.,  December,  1896,  p.  8. 

2  The  Role  of  Different  Proteins  in  Nutrition  and  Growth. 
»  Arch.  Int.  Med.,  1917,  xix,  56. 


GENERAL  CONCLUSIONS  129 

indivisable  unit  of  living  matter.  The  ''micelle"  is  the 
organ  of  intracellular  nutrition  which  by  the  stability  of  its 
chemical  composition  and  the  resulting  physical  constitution 
maintains  the  specificity  of  different  tissues  and  of  each 
species  and  determines  the  cycle  of  evolution  of  each  cell. 
Separated  into  the  salts,  lipoids,  and  amino-acids  which 
compose  it,  the  ''micelle"  no  longer  possesses  any  specificity 
nor  any  of  those  properties  which  characterize  living  matter. 

What  is  the  mechanism  of  the  autoreconstruction  of  the 
living  "micelle?"  The  most  recent  researches  mentioned 
above  oblige  us  to  assume  that  animal  "micelles"  can  assimi- 
late untransf  ormed  amino-acids  and  they  cease  to  live  if  they 
have  not  certain  preformed  amino-acids  (tryptophane)  at 
their  disposal;  which  suggests  that  they  are  incapable  of 
constructing  these  substances  from  the  simplest  chemical 
units.  Van  Slyke  has  shown  that  tissues  absorb  amino-acids: 
the  presence  of  amino-acids  in  the  blood  has  been  proved 
by  Delaunay  and  the  works  of  Fischer,  Kossel,  and  others  on 
the  polypeptids  permit  us  to  conceive  of  the  construction 
of  a  biologic  particle  of  a  still  more  complex  composition 
and  constitution. 

Is  there  a  ferment  analogous  to  that  which  hydrolyzes 
albumins,  which  causes  the  synthesis  of  albumins?  That  is 
hardly  probable.  If  we  imagine  that  a  "micelle"  of  a  certain 
composition  can  attract  and  assimilate  by  a  total  of  its 
physicochemical  properties,  the  amino-acids  of  which  it  is 
composed,  as  a  crystal  attracts  and  fixes  by  analogous 
properties  molecules  identical  to  those  of  which  it  is  formed, 
we  can  readily  understand  the  autoreconstruction  of  par- 
ticles of  the  plasma  with  the  materials  which  are  found  in 
abundance  in  the  medium  in  which  they  are  constantly 
bathed:  and  we  do  not  need  to  consider  a  "ferment"  whose 
existence  has  at  the  present  time  never  been  proved. 

When  the  "micelles"  are  free  in  a  state  of  fluid,  the  colloid 
is  in  the  state  of  sol;  when  they  are  in  unity  in  granules  the 
colloid  is  in  the  state  of  gel  and  in  a  living  organism  these 
two  states  are  always  in  unstable  equilibrium;  each  "micelle" 
is  constantly  in  a  state  of  change  between  gel  and  sol.  Every 
sudden  stop,  every  rupture  of  equilibrium  in  this  continuity 
9 


130  GENERAL  CONCLUSIONS 

of  exchange  and  in  the  passage  between  sol  and  gel,  every 
stabilization  of  one  or  the  other  of  these  states  results  in 
more  or  less  severe  disturbances  of  stabilization  which  in 
turn,  depend  upon  the  dose  and  preparation  of  the  stabilizing 
agent. 

The  biochemical  experience  of  Loewe,  of  which  the  true 
significance  has  been  brought  to  light  by  the  studies  of  Ame 
Pictet  on  the  life  and  death  of  plasma,  definitely  confirm 
these  ideas  and  allow  us  to  understand  the  probable  chemical 
mechanism.  Loewe  found  that  those  substances  which  are 
poisonous  for  living  plasma  and  exercise  no  appreciable 
action  on  dead  albumin,  act  chemically  by  transforming 
unstable  linear  compounds  into  relatively  stable,  cylic  com- 
pounds and  Pictet  drew  from  this  work  the  conclusion  con- 
firmed by  new  and  very  ingenious  experiments  that  it  was 
this  chemical  stabilization  added  to  the  durable  stabilization 
of  a  certain  state  of  biologic  equilibrium  which  might  be  the 
cause  of  a  pathologic  state  of  the  plasma  of  the  cell  and  of  its 
death. 

It  may  be  that  as,  for  example,  in  the  case  of  mercury 
salts  and  certain  venins  by  acting  not  on  the  molecule  but 
on  the  "micelle,"  the  same  product  produces  the  stabiliza- 
tion of  the  colloid  in  various  forms:  gel,  sol,  etc.,  according  to 
the  quantity  or  the  proportion  of  the  product  which  is  fixed : 
and  that  the  rupture  of  equilibrium  in  certain  "micelles" 
will  in  a  sense,  necessarily  result  in  a  contrary  reaction  in 
other  "micelles." 

All  substances,  salts  as  well  as  colloids,  may  disturb  vital 
functions,  that  is  to  say,  the  functions  of  nutrition  of  colloids, 
and  hence  of  the  cells  by  virtue  of  their  being  in  solution  in 
the  interior  of  the  organism  and  of  possessing  affinities  for 
the  substances  which  compose  the  cells. 

From  the  chemical  point  of  view  these  substances  can  be 
divided  into  two  great  groups— those  which  are  nutritive  and 
those  which  are  not.  In  the  first  category  will  belong  all  the 
substances  which  normally  enter  into  the  composition  of  the 
organism;  in  the  second  those  of  which  analysis  shows  no 
trace.  The  alimentary  composition  of  all  organisms  is  very 
uniform  but  the  relative  proportions  in  which  the  different 
elements  are  found  differ  infinitely. 


GENERAL  CONCLUSIONS  131 

Specific  differences  are  very  probably  determined  by  the 
arrangement  and  by  the  proportions  of  different  amino- 
acids,  the  quantities  of  mineral  substances,  iron,  arsenic, 
potassium,  sodium,  magnesium,  calcium,  etc.,  which  vary 
widely  from  one  species  to  another  and  by  the  ties  which 
bind  amino-acids  into  "micelles." 

Nutritive  salts  are  fixed  in  definite  proportions :  the  excess 
being  rapidly  eliminated.  Non-nutritive  salts  may  be  neutral 
and  then  are  rapidly  eliminated  but  they  are  pathogenic 
whenever  their  quantity  disturbs  the  sol-gel  equilibrium  of 
the  colloids.  Nutritive  salts,  like  pathogenic  salts,  will  not 
produce  the  formation  of  specific  antibodies  because  the 
reactions  between  salts  are  innocuous  and,  furthermore, 
because  a  salt  produced  in  excess  is  rapidly  eliminated. 

Colloids  may  also  be  nutritive,  neutral  or  pathogenic  but 
only  after  having  undergone  a  complete  digestion,  that  is  to 
say,  a  disintegration  into  free  molecules.  They  will  always 
be  pathogenic,  when  in  the  colloidal  state  they  have  pene- 
trated by  any  way  whatever  into  the  interior  of  the  organism 
which  must  then  digest  them,  without  being  specifically 
adapted  for  this  function.  Certain  colloids  (toxins)  composed 
of  very  small  "micelles"  may  be  directly  pathogenic,  when 
they  are  fixed  "en  surcharge"  to  certain  cells.  On  the 
other  hand,  other  colloids  with  more  voluminous,  less  pene- 
trating "micelles"  do  not  become  pathogenic  until  after  a 
longer  or  shorter  incubation  period ,  when  having  entered  the 
cell  and  distended  its  membrane  by  the  multiplication  of 
normal  antibodies,  they  become  able  to  penetrate  to  the 
interior  of  the  cells.  In  one  case  as  in  the  other  the  cells  not 
fatally  attacked  will  transform  the  colloid  antigen  into  nutri- 
tious or  eliminable  crystalloids  and  will  multiply  the  trans- 
forming substance  which  will  then  become  antibody  in  excess. 

This  antibody  in  excess  will  be  specific  because  the  colloid 
antigens  are  specific  individually  and  the  antibody  will 
accumulate  in  the  cells  and  in  the  organism  because  as  much 
as  we  know  of  it,  it  is  a  colloid.  The  production  of  antibody 
in  excess  is  a  vital  reaction  of  the  cells.  Whenever  the  anti- 
body in  excess  forms  with  its  antigen  an  insoluble  compound, 
there  results  an  increase  in  the  degree  of  immunity  and  at 


132  GENERAL  CONCLUSIONS 

the  same  time  of  the  natural  sensitiveness  or  anaphylaxis. 
In  every  case,  for  salts  as  well  as  colloids,  the  differences  and 
the  same  contrasts  in  the  reactions  (nutritive,  immunizing 
or  pathogenic)  will  be  determined  by  the  proportion  of  the 
reacting  substances. 

A  pathogenic  bacterium  will  naturally  obey  the  same 
general  biochemical  law  as  any  other  cell  in  order  to  nourish 
itself  in  the  interior  of  the  organism  to  which  it  has  pene- 
trated. If  by  its  albumins  or  by  its  secretions,  it  is  antigenic 
for  the  cells  of  the  organism  the  albumins  or  secretions  of 
these  latter  are  antigenic  for  it  and  like  the  organism  the 
bacterium  will  produce  antibodies  intra-  and  extracellular 
against  these  antigens.  At  the  same  time  it  will  become 
more  immune  and  more  sensitive  and  whenever  the  organism 
produces  its  antibodies  more  rapidly  than  the  infecting 
bacterium,  the  bacterium  will  succumb  to  anaphylaxis.  It 
will  be  autolized  or  surcharged  with  antibody  or  antigen 
(sensitized)  and  will  become  the  easy  prey  of  phagocytes  on 
account  of  the  phenomenon  of  positive  chemotaxis  of  Charles 
Bordet  and  Massart.  In  this  way  the  conditions  of  normal 
or  pathologic  nutrition  of  a  "micelle"  and  in  consequence  of 
the  cell  may  be  understood. 

In  an  organism  composed  of  a  combination  of  different 
tissues,  and  of  organs  and  glands  with  special  functions, 
reactions  will  obviously  be  much  more  complex.  In  these 
cases  a  disturbance  will  never  be  strictly  limited ;  it  will  have 
always  multiple  eft'ects.  The  intervention  of  the  liver,  spleen, 
suprarenal  capsule,  thyroid  and  parathyroid  glands,  hypo- 
physis and  especially  the  central  nervous  system  may  greatly 
modify  the  rate  of  each  reaction,  and  may  infinitely  compli- 
cate the  study  of  its  mechanism.  But  whatever  these  com- 
plications may  be,  whether  the  objective  symptoms  are 
caused  by  a  purely  local  reaction  or  whether  caused  by  a 
reflex  action,  it  is  impossible  to  imagine  that  any  modifica- 
tion whatever  in  the  normal  state  of  the  organism  could  be 
produced  by  anything  other  than  a  disturbance  of  the  nutri- 
tion of  the  "micelle";  in  other  words,  by  a  modification  of 
the  physicochemical  equilibrium  of  the  "  micelles." 


.       GENERAL  CONCLUSIONS  133 

Summary.— All  the  studies  on  physical  ch(emistry  and 
normal  and  pathologic  biology  tend  to  prove  that  the  ele- 
mentary chemical  composition  of  albumins  and  of  living 
beings  is  very  uniform  and  that  the  specific  differences  are 
caused  only  by  differences  in  the  proportions  in  which  these 
elements  are  united  into  "micelles."  All  albumins  are  con- 
structed on  the  same  plan.  Their  reactions  are  therefore  all 
of  the  same  nature  but  the  chemical,  osmotic  and  physiological 
equilibria  determined  by  the  different  proportions  of  the 
elements  which  constitute  the  "micelles,"  vary  infinitely, 
so  that  they  can  react  differently  to  the  same  reacting 
substance. 

The  chemical  and  physiological  unit  of  the  plasma  is  the 
"micelle"  which  possesses  for  each  animal  or  vegetable  species 
a  particular  and  constant  chemical  and  osmotic  equilibrium. 

A  "micelle"  can  be  nourished  only  by  the  crystalloids  of 
which  it  is  composed,  and  can  assimilate  them  without 
trouble  only  in  the  proportions  in  which  it  normally  contains 
them.  It  may  absorb  them  and  fix  them  in  different  propor- 
tions but  then  its  equilibrium  is  changed  and  it  is  easy  to 
imagine  that  by  absorbing  a  foreign  substance  (salt  or 
crystalloid)  in  progressively  increasing  quantity  and  over  a 
sufficiently  long  time  in  order  that  the  new  state  of  equilib- 
rium may  become  hereditary,  a  "micelle,"  a  plasma,  or  a 
cell  may  acquire  new  properties  which  will  constitute  a  new 
race  or  even  a  new  species. 

A  cell  may  absorb  specifically  different  "micelles"  but  it 
cannot  incorporate  them  as  such  into  its  own  plasma  because 
they  possess  a  different  nutritive  equilibrium.  It  cannot 
directly  be  nourished  by  them  without  first  demolishing 
them  because  the  "micelles"  cannot  absorb  other  "micelles" 
but  only  non-specific  crystalloid  compounds  which  come  to 
them. 

Heterogeneous  particles  are  thus  necessarily  dissociated 
when  they  come  into  a  medium  foreign  to  themselves  and 
this  process  of  intracellular  dissociation  is  the  origin  of  simple 
immunity  on  the  one  hand  or  of  immunity-anaphylaxis  on 
the  other  according  to  the  rate  of  the  reactions  produced 
and  according  as  the  formation  of  antibody  in  excess  neutral- 


134  GENERAL  CONCLUSIONS 

izes  antigens  outside  of  the  cells,  and  prevents  the  direct  and 
too  rapid  transformation  of  one  foreign  species  to  another. 

Thus  in  the  last  analysis,  an  organisni  can  be  nourished 
only  by  simple  chemical  compounds  and  can  assimilate 
them  only  in  proportions  identical  to  those  in  which  th^y 
are  composed  in  its  colloidal  complexes.  The  absorption 
by  the  interior  of  the  organism  of  a  complex  of  different 
composition  and  constitution  will  always  result  in  the  creation 
of  a  new  and  abnormal  state  of  equilibrium. 

This  is  a  general  biologic  law  applicable  to  all  the  mani- 
festations of  living  matter  without  excepting  the  evolution 
of  conscience  and  the  formation  of  states  of  mind.  In  fact 
in  analyzing  the  evolution  of  thought  we  find  that  a  mind 
can  directly  absorb  only  simple  ideas  and  can  assimilate 
them  without  trouble  only  in  proportions  identical  to  those  in 
which  its  own  complex  of  ideas  is  formed.  Complexes  of 
ideas  foreign  to  its  understanding  and  which  one  may  com- 
pare to  specifically  different  "micelles"  can  be  assimilated 
only  on  condition  that  they  can  be  digested,  that  is  to  say, 
can  be  analyzed  or  dissociated.  If  this  is  so,  a  state  of  simple 
immunity  or  immunity-anaphylaxis,  a  new  state  of  psychic 
equilibrium  will  result  by  a  process  analogous  to  that  which 
induces  modifications  in  the  states  of  chemical  and  physio- 
logical equilibrium  of  "micelles"  and  cells.  A  new  theory, 
a  new  religion,  a  new  political  or  social  system  introduced  too 
suddenly  or  in  too  large  a  dose  into  subjects  insufficiently  or 
badly  prepared  will  always  upset  the  normal  equilibrium. 
This  is  a  pathologic  state,  quite  as  serious  in  the  soul  of 
individuals  and  of  societies  as  too  large  a  dose  of  antigens 
in  the  cell  and  in  the  organism. 


PART  II. 


CHAPTER  X. 

EVOLUTION  OF  THEORIES  CONCERNING 

IMMUNITY,  ANAPHYLAXIS  AND 

ANTI-ANAPHYLAXIS. 

INTRODUCTION. 

Since  the  origin  of  infectious  diseases  has  been  recognized, 
we  have  tried  to  treat  or  prevent  them  by  methods  based 
on  the  reactions  produced  in  the  infected  organism  by  patho- 
genic bacteria  or  by  bacterial  products  (toxins).  In  this 
research,  only  immediate  results  were  considered:  active 
immunity  by  preventive  vaccination  or  by  bacteriotherapy, 
or  passive  immunity  by  serum  therapy.  In  both  cases,  the 
vaccinated  or  recovered  organism  was  considered  normal. 
In  addition  to  these  diseases,  correctly  designated  as  infec- 
tious, with  acute  evolution  (typhoid  fever,  cholera,  plague, 
pneumonia,  etc.)  or  chronic  (tuberculosis,  syphilis,  malaria, 
etc.),  there  are  a  great  number  of  chronic  morbid  states  such 
as  gastro-intestinal  troubles,  asthma,  various  dermatoses, 
rheumatisms  and  arthritides,  neurasthenias,  etc.,  of  unknown 
origin. 

These  diseases  are  not  contagious;  we  cannot  assign  a 
direct  bacterial  origin  to  them.  Nevertheless  they  present 
many  analogies  in  their  evolution  and  symptoms  with  true 
infections  or  with  the  consequences  of  such  infections  (tuber- 
culosis, syphilis,  diphtheria,  influenza,  etc.). 

Since  the  general  use  of  vaccines,  such  as  dead  bacteria, 
curative  sera  or  certain  drugs  of  complex  composition,  such 
as  the  arsenobenzenes,  quinine,  antipyrin,  chaulmoogra  oil, 
peptones;  it  has  been  found  that  reactions  which  are  identical 


136  THEORIES  CONCERNING  IMMUNITY 

with  those  caused  by  bacteria  or  bacterial  products  may  be 
caused  by  inert  substances :  identical  because  they  are  directly 
or  indirectly  antigenic.  The  introduction  of  these  substances 
into  the  organism  causes  in  the  organism  the  formation  of 
more  or  less  specific  antibodies,  and  it  has  been  found  that 
mixtures  prepared  in  vitro  of  antibodies  with  their  correspond- 
ing antigens  are  either  neutral  or  toxic:  neutral  when  they 
remain  clear  (toxins  and  antitoxins);  toxic  when  they  pre- 
cipitate (bacteria  or  sera  and  their  antibodies) . 

Similar  results  are  obtained  in  mw— when  an  animal  is 
injected  with  an  antigen  which  is  precipitated  by  its  serum. 

The  necessary  conclusions  are  that : 

1.  In  those  diseases  where  an  antibody  is  formed  which 
can  precipitate  its  antigen,  pathologic  manifestations  are 
caused  precisely  by  the  very  excess  of  this  antibody. 

2.  The  same  pathologic  manifestations  can  be  caused  by 
inert  antigenic  substances. 

3.  In  many  cases  the  origin  of  a  chronic  disease  is  not  the 
direct  action  of  a  toxic  substance  itself,  but  a  secondary 
reaction  between  the  organism  and  an  antigen  which  may  in 
itself  be  innocuous— for  example,  a  harmless  bacterium, 
normal  serum,  or  egg-white. 

4.  Finally,  in  order  to  obtain  an  exact  and  complete  idea 
of  the  state  of  an  immunized  organism,  it  is  not  sufficient 
to  consider  the  accrued  resistance  to  a  definite  pathogenic 
agent;  but  one  must  also  consider  the  results  which  this 
state  of  immunity,  that  is  to  say,  the  excess  of  antibody 
present  in  the  blood  and  produced  by  the  organs,  may  have 
on  the  nutrition-equilibrium  of  the  immunized  organism. 

But  a  mere  statement  does  not  suffice.  To  convince  the 
reader,  it  is  necessary  to  produce  the  "proceedings  of  the 
court,"  and  to  go  over  again  the  stages  of  the  road  traveled 
by  experimental  biology  since  the  time  of  Pasteur. 

RESEARCHES  BY  PASTEUR,  BY  ROUX  AND  YERSIN  AND 
BY  BEHRING  AND  KITASATO. 

The  researches  by  Pasteur  and  by  his  school  have  brought 
out  four  fundamental  biological  rules  or  laws: 


RESEARCHES  BY  PASTEUR  137 

1.  All  contagious  diseases  are  caused  by  living  bacteria, 
which  multiply  in  the  blood  or  in  the  tissues  of  the  invaded 
organism  or,  in  other  words:  All  bacteria  able  to  multiply 
and  to  live  more  or  less  steadily  in  the  blood  or  in  the  tissues 
of  a  superior  organism,  may  cause  infectious  diseases  which 
are  directly  or  indirectly  contagious. 

2.  Bacteria  are  pathogenic  because  of  the  poisons  which 
they  secrete  or  produce. 

3.  The  virulence  of  pathogenic  bacteria  may  be  attenuated 
or  completely  suppressed  in  certain  cases  by  artificial  cultures 
and  may  be  increased  by  passage  through  living  organisms. 

4.  The  introduction  into  an  animal  organism  of  a  patho- 
genic bacteria  attenuated  or  sterilized,  protects  this  organism 
against  later  infection  by  the  same  bacteria  when  virulent. 
The  "vaccinated"  animal  thus  acquires  an  active  immunity, 
and  it  is  important  to  note  that  this  immunity  appears  only 
after  an  "incubation  period,"  which  varies  in  time  for  the 
different  infectious  bacteria  from  eight  to  fourteen  days,  and 
which  lasts  for  several  days  at  least. 

Several  years  later,  the  researches  of  Roux  and  Yersin  on 
the  "toxin"  of  diphtheria,  led  Behring  and  Kitasato  to  the 
discovery  of  antitoxin;  their  researches  showed  that: 

5.  By  the  injection  into  an  animal  of  a  bacterial  poison 
in  non-pathogenic  or  slightly  pathogenic  quantity,  the  animal 
acquires  at  first  a  greater  resistance  to  the  same  poison,  and 
later,  when  the  treatment  is  continued,  there  is  produced  in 
the  blood  of  the  animal  a  specific  antidote,  exclusively  for  this 
poison.  The  injection  of  a  toxin  causes  the  production  of  an 
antitoxin  in  the  organism.  The  antitoxin  neutralizes  in 
vitro  and  in  vivo  the  pathogenic  action  of  the  toxin.  The 
product  of  a  mixture  of  toxin  with  antitoxin,  in  suitable 
proportions,  is  neutral. 

These  were  the  fundamental  rules  on  which  was  based  all 
ulterior  research  concerning  reactions  between  the  infecting 
bacteria  and  the  infected  organisms.  It  was  then  generally 
thought  that,  on  the  basis  of  these  rules,  one  would  succeed 
rapidly  and  without  too  many  difficulties  in  cultivating  or  at 
least  in  demonstrating  the  bacteria  of  all  infectious  diseases, 
and  in  preparing  preventive  vaccines  or  curative  sera  for  all 


138  THEORIES  CONCERNING  IMMUNITY 

these  diseases.  It  was  hoped  that  in  the  course  of  this 
research  it  would  become  possible  to  explain  at  the  same  time 
the  mechanism  of  all  these  reactions— namely,  why  a  bac- 
terium is  pathogenic  or  may  become  so,  how  and  why  an 
infected  organism  may  spontaneously  recover  or  succumb 
to  the  disease,  whether  all  infectious  diseases  have  the  same 
evolution— and  also  why  the  reactions  caused  by  bacteria 
or  by  their  toxins  differed  from  the  reactions  caused  by  most 
toxic  salts,  inorganic  or  organic. 

In  reality  these  investigations  have  met  with  difficulties 
as  numerous  as  they  were  unforeseen.  Even  today,  after 
half  a  century  of  relentless  labor,  there  are  very  contagious 
diseases,  such  as  measles,  scarlatina,  typhus,  hydrophobia,  of 
which  the  germs  are  unknown;  there  are  others  such  as  leprosy 
malaria,  the  trypanosomiases,  of  which  the  germs  are  known 
but  which  cannot  yet  be  cultivated  on  artificial  media;  there 
are  others  for  which  we  have  not  succeeded  in  preparing  either 
preventive  vaccine  or  curative  serum;  lastly,  there  are  others 
(psoriasis,  eczema,  cancer,  etc.)  which  are  not  contagious 
and  of  which  the  germs  are  unknown,  but  which  have  many 
characteristics  in  common  with  diseases  of  infectious  origin. 

It  was  therefore  necessary  to  recognize  that  all  these 
problems  could  not  be  solved  by  frontal  attacks;  that  if,  in 
certain  cases,  it  was  possible  to  arrive  at  practical  solutions 
by  avoiding  obstacles,  and  that  if  it  was  possible  to  discover 
preventive  vaccines  or  curative  treatments  without  knowing 
the  causes  of  the  disease— Jenner  for  small-pox  and  Pasteur 
for  hydrophobia— in  many  other  cases  it  was  necessary,  in 
order  to  arrive  at  the  same  results,  to  make  a  long  detour 
in  the  attempt  to  better  understand  the  functions  of  the 
organism,  and  the  nature  and  mechanism  of  its  normal  and 
pathologic  reactions. 

And  thus  it  is  that  nearly  all  the  exact  and  biological 
sciences,  chemistry  and  physics,  general  biology  together 
with  medicine  and  bacteriology,  have  been  drawn  upon  to 
attack  the  immunity  problem  from  several  angles  at  the 
same  time.  What  often  happens  in  the  exploration  of 
unknown  lands  has  occurred  here:  In  following  different 
trails,  the  explorers  lose  sight  of  each  other  at  times,  their 


TRANSFUSION  OF  BLOOD  139 

discoveries  lead  to  results  which  are  apparently  irreconcilable, 
and  contrary  to  the  general  ideas  which  inspired  their 
departure;  yet  in  the  end  all  these  routes  lead  to  a  clearing 
from  which  one  can  survey  easily  all  the  roads,  and  where 
everything  can  be  explained  and  mutually  understood. 

During  the  study  of  immunity  such  phenomena  have  been 
discovered  that  it  seemed  impossible  to  find  common  bonds, 
or  to  reconcile  them  with  the  laws  which  logically  followed 
the  discoveries  of  Pasteur;  we  shall  see  that  it  has  become 
possible  today  to  assemble  all  these  phenomena  into  one 
harmonious  whole  which,  far  from  contradicting,  confirms 
Pasteur's  ideas  and  completes  them  by  new  laws. 

TRANSFUSION  OF  BLOOD  AND  INJECTION  OF  HETER- 
OLOGOUS AND  HOMOLOGOUS  SERA  AND 
OTHER  PROTEINS. 

For  a  long  time  (since  the  old  Egyptians)  it  was  known 
that  it  was  possible  to  ''transfuse"  blood  from  one  animal 
to  another,  and  that  transfusion  between  animals  of  the 
same  kind  was  less  dangerous  than  transfusion  between 
animals  of  different  kinds;  but  it  was  to  Landois,  and  espe- 
cially to  Hayem^  (1885-1890)  that  we  owe  the  first  precise 
experimental  studies  of  this  question.  Among  other  experi- 
ments Hayem  injected  blood  from  cattle  into  the  veins  of 
dogs,  and  determined  that  while  a  first  injection  of  about 
50  c.c.  is  endured  without  noticeable  reaction,  a  second 
injection,  of  a  dose  half  as  strong,  into  the  same  animal  twelve 
days  after  the  first  injection,  is  followed  several  minutes 
later  by  a  violent  crisis  generally  ending  in  death. 

"The  blood  of  an  animal  so  treated,"  writes  Hayem,  "con- 
tains elements  more  or  less  changed,  and  sometimes  hyaline 
concretions  which  are  very  refracting  and  extremely  viscous. 
The  blood  in  a  tied  vessel,  kept  from  the  previous  day, 
remained  liquid;  there  was  a  formation  of  clots  like  a  sedi- 
ment. It  is  these  small  masses  of  albuminoid  matter  (forma- 
tion of  a  precipitate)  which  are  the  origin  of  the  emboli. 

^  On  Blood  and  its  Anatomical  Alterations,  Paris,  1889,  pp.  240  et  seq. 


140  THEORIES  CONCERNING  IMMUNITY 

When  they  are  very  numerous  and  able  to  obstruct  the  cir- 
culation more  or  less  completely,  the  animal  soon  succumbs; 
but  it  is  conceivable  that  in  certain  cases,  they  may  deter- 
mine local  lesions  of  small  size  and  the  animals  may  survive." 

Other  similar  experiments  convinced  this  savant  that  the 
injection  of  blood  from  cattle  into  dogs  represents  only  one 
special  case  of  this  kind  of  "coagulating  injection,"  so  that 
one  may  generalize  this  fact  and  say: 

The  second  injection  of  blood  or  of  a  heterologous  albumi- 
noid substance  (from  an  animal  of  a  different  kind)  into  the 
veins  of  an  animal  several  days  after  the  first  injection,  is 
much  more  dangerous  than  the  first. 

The  first  injection  of  a  strong  dose  is  usually  well  endured, 
the  second  and  lesser  dose  is  usually  fatal. 

The  second  dose  is  pathogenic  because  it  causes  the  forma- 
tion of  a  precipitate  which  obstructs  the  capillaries. 

Hayem  pointed  out  this  phenomenon  without  endeavoring 
to  explain  it,  so  that  his  discovery  did  not  awaken  at  that 
time  the  interest  which  it  deserved. 

It  was  only  several  years  later  (1894-1900)  that  all  its 
importance  was  realized  through  the  works  of  Pfeiffer, 
Metchnikoff,  J.  Bordet,  Kraus,  Belfanti  and  Carbone,  and 
others,  on  the  reciprocal  reactions  between  the  sera  of 
immunized  animals,  on  the  one  hand,  and  bacilli,  the  broth 
cultures,  sera,  blood  elements,  or  other  injected  cells,  on  the 
other.  Thus  Pfeiffer  determined  that  cholera  vibrios  injected 
into  the  peritoneal  cavity  of  a  guinea-pig,  previously  immun- 
ized against  these  bacilli,  were  agglutinated  and  partially 
destroyed  in  the  peritoneal  fluid,  without  direct  intervention 
of  phagocytes. 

Soon  after,  Metchnikoff,  followed  by  J.  Bordet,  showed 
that  the  same  phenomena  could  be  reproduced  in  vitro  by 
mixing  in  a  test-tube  a  culture  of  cholera  vibrios  with  a  small 
amount  of  serum  from  an  immunized  animal. 

Kraus  obtained  the  same  result,  not  only  for  cholera, 
typhoid  and  plague  bacteria,  but  also  for  the  filtrated  broth 
cultures  of  these  microbes.  In  mixing  these  broth  cultures 
with  a  little  serum  from  immunized  animals,  he  saw  the 
formation  of  a  precipitate. 


TRANSFUSION  OF  BLOOD  141 

Soon  afterward,  Belfanti  and  Carbone  (July,  1898)  dis- 
covered the  very  important  fact  that  the  injection  of  rabbit 
serum  into  a  horse  made  the  serum  of  this  horse  toxic  for  all 
rabbits;  and  Bordet  completed  this  experiment  by  showing 
that  the  serum  of  any  animal  injected  with  the  blood  of  an 
animal  of  different  kind,  acquires  the  property  of  agglutinat- 
ing and  dissolving  the  red  corpuscles  and  of  forming  a  pre- 
cipitate with  the  serum  of  the  animal  which  furnished  the 
injected  blood,  on  mixing  both  liquids  in  a  test-tube. 

The  reactions  observed  in  vitro  therefore  allow  us  to  per- 
ceive what  goes  on  in  the  organism,  and  to  explain  the 
nature  if  not  the  fundamental  mechanism  of  a  series  of 
pathological  reactions  that  might  from  this  time  on  have  led 
us  to  regard  immunity  and  the  pathogenicity  of  certain 
infectious  diseases  in  a  new  light. 

The  results  of  the  experiments  of  Hayem,  Behring  and 
Kitasato,  Pfeiffer,  Metchnikoft',  J.  Bordet,  Kraus,  Belfanti 
and  Carbone,  and  others,  has  been  to  emphasize  the  follow- 
ing biological  rules: 

1.  The  injection  of  a  heterologous  albumin  (bacterial 
bodies,  blood,  serum,  casein,  etc.)  or  of  a  non-albuminoid 
bacterial  product  causes,  in  the  injected  organism,  the  forma- 
tion of  a  substance  in  excess  which  possesses  a  specific 
affinity  for  the  injected  substance. 

The  name  of  "antibody"  has  been  given  to  all  the  substances 
thus  formed,  and  of  ''antigen"  to  all  those  substances  causing 
such  a  formation. 

2.  The  antibodies  neutralize  in  vitro  and  in  vivo  the  specific 
pathogenic  action  of  the  antigen  toxin  and  of  the  infectious 
antigen  bacilli;  but  whereas  the  mixtures  of  antigen  toxins 
(non-albuminoid)  with  their  antitoxins  give  a  product  which 
is  soluble  "in  vitro''  and  neutral  in  the  organism— the  mix- 
tures of  the  infectious  antigen  bacilli  with  their  antibodies 
give  a  product  which  forms  a  precipitate.  This  precipitate 
is  neutral  from  an  infectious  point  of  view  in  the  case  of 
pathogenic  bacilli,  and  from  a  toxic  point  of  view  for  toxal- 
bumins,  but  in  itself  it  is  endowed  with  a  special  toxicity. 

This  special  toxicity  becomes  evident  when  one  eliminates 
from  the  mixture  the  actual  "toxin"  or  "infection"  as  for 


142  THEORIES  CONCERNING  IMMUNITY 

example  by  mixing  with  their  respective  antibodies  harmless 
albumin-antigens  (like  serum,  casein,  white  of  egg,  etc.) 
which  are  not  toxic  in  themselves.  For  in  such  cases,  the 
two  substances,  each  of  them  inoffensive,  form  a  product— a 
precipitate— which  is  toxic. 

The  pathologic  manifestations  caused  by  these  toxic  mix- 
tures are  always  the  same,  regardless  of  the  nature  of  the 
antigen-albumin  (pathogenic  bacillus,  toxalbumin  or  ordi- 
nary food  albumin) . 

It  follows  by  deduction  that : 

The  reactions  caused  by  the  toxic  products  of  mixtures 
in  vitro  or  in  vivo  of  antibodies  with  their  antigens,  always 
affect  the  same  organs  and  are  always  of  the  same  nature. 

What  is  the  nature  of  this  reaction,  and  what  justifies  it? 

It  may  be  assumed,  with  Metchnikoff  and  his  school,  that 
the  heterologous  albumins  like  bacteria,  undergo  intracellular 
digestion  in  the  blood  and  in  certain  organs.  Anti-infectious 
immunity  through  phagocytosis  would  be  only  a  particular 
case  of  this  intracellular  digestion,  or  quoting  Bordet,  "a 
fortunate  and  efficient  application,  for  the  defense  of  the 
organism,  of  a  primordial  function  which  would  exist  to  the 
same  extent  even  if  there  were  no  pathogenic  germs  on  the 
surface  of  the  earth."  This  theory,  however,  does  not  explain 
the  pathological  manifestations  which  result  from  this 
function.  It  does  not  explain  and  does  not  try  to  explain, 
which  substances,  innocuous  when  first  injected,  become 
pathogenic  at  the  second  injection,  whereas  true  toxins,  on 
the  contrary,  become  innocuous  under  the  same  conditions. 

These  discoveries  were  registered  without  connection  with 
any  general  biological  phenomena,  and  these  questions  had 
to  remain  unanswered  for  a  long  time. 

ANAPHYLAXIS. 

It  is  evident  that  for  minds  that  were  neither  prejudiced 
nor  governed  by  the  theories  of  the  time  which  inspired  all 
the  foregoing  experiments,  the  general  rules  which  we  have 
just  formulated,  contained  already  at  this  time  (1897-1898) 
all  the  elements  which  compose  the  phenomenon  of  anaphy- 


ANAPHYLAXIS  143 

laxis,  and  that  they  even  gave  a  sufficiently  clear  explanation 
of  its  mechanism. 

In  spite  of  all  the  foregoing  experiments  it  was  as  a  dis- 
covery of  a  new  phenomenon  that  most  biologists  regarded 
anaphylaxis  when  introduced  by  Charles  Richet  and  Portier 
in  1902. 

These  scientists  discovered  that  an  albuminoid  substance 
called  actino-congestion,  extracted  from  the  tentacles  of 
sea-anemones,  when  injected  into  the  veins  of  dogs,  was 
toxic  at  certain  doses,  and  innocuous  at  feebler  doses.  Con- 
gestion should  therefore  have  been  regarded  as  a  toxin,  and 
behave  as  such:  The  injection  of  a  non-lethal  dose  into  an 
animal  should  have  vaccinated  it  against  a  later  injection 
of  a  dose  fatal  for  the  control  animals. 

To  their  great  surprise,  the  experimenters  had  to  record 
a  result  which  was  exactly  the  contrary. 

''The  characteristic  experiment,"  writes  Charles  Richet,^ 
''the  one  which  showed  the  phenomenon  in  all  its  indis- 
putable clearness,  was  made  on  the  dog  Neptune.  This  was 
an  animal  of  exceptional  strength  and  health.  He  first 
received  0.1  c.c.  glycerinated  extract  of  sea-anemone  ten- 
tacles without  becoming  ill.  Twenty-two  days  later,  as  he 
was  in  excellent  health,  I  injected  the  same  dose  of  0.1  c.c. 
A  few  seconds  after  the  injection,  he  became  very  ill;  respira- 
tion became  painful  and  panting.  He  could  hardly  drag 
himself  along,  lay  down  on  his  side,  was  seized  with  diarrhea 
and  bloody  vomiting.  Sensation  disappeared  and  he  died 
in  twenty-five  minutes." 

Having  thus  obtained  a  reaction  contrary  to  vaccination  or 
prophylaxis,  Richet  called  this  phenomenon  "anaphylaxis." 

Neither  Richet,  nor  all  those  who  were  interested  in  these 
experiments,  saw  anything  in  common  between  anaphylaxis 
and  the  phenomena  described  by  Hayem,  Krauss,  Belfanti, 
Bordet,  and  others,  because  it  seemed  hardly  possible  to 
correlate  the  action  of  a  poison  (actinocongestin)  with  that 
of  blood  or  serum  from  animals  of  allied  species  which  were 
obviously  considered  as  essentially  alimentary  substances. 

On  the  other  hand,  it  was  already  known  that  injections 

1  Anaphylaxis,  S.  F.  Alcan,  p.  3. 


144  THEORIES  CONCERNING  IMMUNITY 

of  diphtheria  or  tetanus  toxins  could  be  repeated  at  will 
on  the  same  animal  without  ever  causing  an  anaphylactic 
crisis,  and  that,  on  the  contrary,  the  result  of  these  injections 
had  been  the  formation  in  the  blood  of  the  injected  animal 
of  an  antitoxin  which  neutralized  the  noxious  action  of  these 
toxins. 

Richet  was  therefore  perfectly  justified  in  considering 
anaphylaxis  as  a  new  and  peculiar  phenomenon.  He  speci- 
fies the  conditions  of  its  evolution  by  insisting  on  the  neces- 
sity of  an  "incubation  period"  (as  in  immunity),  during 
which  the  organism  prepares  its  anaphylactic  state  and  he 
explains  it  by  the  formation  of  a  "prepoison"  (toxogenin), 
which  becomes  a  poison  when  in  contact  with  a  new  quan- 
tity of  antigen.  Interpreted  in  this  wlay,  Richet's  discovery 
contributed  a  new  complication  to  the  explanation  of  the 
immunity  process. 

How  and  why  is  toxogenin  formed,  through  what  mechan- 
ism does  it  become  apotoxin  when  it  combines  with  the 
antigen?  These  were  further  questions  that  had  to  remain 
unanswered  at  the  time. 

However,  in  spite  of  ignorance  as  to  explanation  and 
classification,  these  phenomena  created  much  interest, 
exactly  because  they  were  in  formal  contradiction  to  the 
fundamental  principle  on  which  was  founded  not  only  pre- 
ventive vaccination  but  also  the  preparation  of  antitoxic 
sera. 

These  were  questions  which  closely  affected  the  most 
important,  the  most  stirring  problems  of  general  biology. 
It  was  impossible  to  leave  them  in  suspense,  or  to  be  con- 
tented with  provisional,  incomplete  and  often  contradictory 
explanations;  and  in  order  to  arrive  at  more  satisfactory 
answers  it  was  necessary  to  penetrate  still  further  into  the 
mechanism  of  these  reactions.  And  so  research  into  the 
properties  and  the  action  of  heterologous  albumins  became 
the  order  of  the  day  in  every  laboratory  of  experimental 
biology. 

Soon  after  the  publication  of  Richet's  work,  which  con- 
cerned itself  only  with  anaphylactic  shock,  Arthus  discovered 
local  and  chronic  anaphylaxis  by  showing  that  successive 
injections  of  horse  serum  into  rabbits,  no  longer  into  the 


ANTI-ANAPHYLAXIS  OF  ANIMALS  145 

blood  but  under  the  skin,  resulted  in  the  formation  of  indur- 
ated edemas  at  the  point  of  inoculation.  Arthus  found  at 
the  same  time  that  animals  sensitized  by  a  serum  also  become 
hypersensitive  to  peptone  or  to  gelatin,  though  to  a  lesser 
degree;  in  short  that  the  anaphylactic  reaction  is  not  always 
an  exclusively  specific  one. 

Marfan  confirmed  these  experiments  by  the  observation 
of  ''Serum  Disease"  in  children  repeatedly  injected  with 
antidiphtheritic  (horse)  serum. 

In  a  series  of  most  interesting  experiments.  Hamburger 
and  Moro  showed  that  a  heterologous  serum  injected  into 
the  veins  of  an  animal  continues  to  circulate  in  this  animal's 
blood  up  to  the  appearance  of  the  specific  antibody.  It  is  at 
this  moment  that  the  incubation  period  ends,  and  that  the 
animal  becomes  hypersensitive  to  a  new  injection  of  the  same 
substance. 

Besredka  determined  that  this  incubation  period  was 
longer  as  the  quantity  of  heterologous  serum  injected  was 
greater,  and  Friedberger's  researches  completed  this  series  of 
experiments  by  showing  that,  if  an  animal  be  injected  repeat- 
edly with  the  same  serum  in  non-pathogenic  doses,  the  incu- 
bation period  becomes  progressively  shorter,  which  means 
that  the  formation  of  the  antibody  takes  place  progressively 
more  rapidly. 

These  researches,  therefore,  allowed  certain  elements  of  the 
problem  to  be  defined,  but  at  the  same  time,  they  brought 
out  others  of  a  complicating  nature. 

These  facts  as  well  as  the  observations  of  the  unfortunate 
accidents  in  the  preparation  of  antibacterial  sera  already 
caused  the  prediction  that  the  phenomenon  of  anaphylaxis, 
its  causes,  nature  and  mechanism  could  be  regarded,  from  a 
different  and  broader  point  of  view  than  that  which  inspired 
Richet  in  his  experiments  and  in  the  interpretation  of  their 
results. 

ANTI-ANAPHYLAXIS  AND  THE  IMMUNIZATION  OF 
ANIMALS. 

The  discovery  of  antidiphtheritic  serum  naturally  sug- 
gested the  idea  of  trying  in  the  same  way  to  obtain  curative 
10 


146  THEORIES  CONCERNING  IMMUNITY 

sera  for  all  the  infectious  diseases  of  which  the  bacteria  were 
known  and  could  be  cultivated  (cholera,  plague,  t^'phoid 
fever,  tuberculosis,  anthrax,  and  others). 

Horses  and  other  animals  were  therefore  injected,  first 
with  sterilized  cultures,  then  with  attenuated  and  lastly 
with  virulent  cultures  of  these  bacilli,  repeating  these  injec- 
tions for  weeks  and  months  and  increasing  the  doses.  Rarely 
was  the  desired  result,  that  is,  a  really  active  serum,  obtained. 
The  animals  so  treated  became  immune,  it  is  true,  never 
suffered  from  plague  or  typhoid  fever,  but  the  subcutaneous 
injections  caused  the  formation  of  edemas,  abscesses  and 
other  lesions  which  complicated  the  treatment,  while  animals 
into  whose  veins  the  injections  were  made  often  died  on  the 
very  instant  or  several  minutes  after  the  injection,  They 
fell  as  if  knocked  down,  and  died  after  a  few  convulsions. 
It  was,  therefore,  Arthus's  local  anaphylaxis  or  Richet's 
anaphylactic  shock  which  were  in  these  instances  caused 
by  bacterial  injections,  and  which  complicated  the  process 
of  immunization. 

In  this  way  it  was  confirmed  that  living  or  dead  pathogenic 
bacteria,  and  in  certain  cases,  also  the  filtered  broth  cultures 
were  able  to  cause  in  the  organism  the  same  reactions  as 
alimentary  or  toxic  albumins. 

Rarely  could  this  be  observed  in  the  practice  of  preventive 
vaccinations  because,  in  order  to  protect  the  organism 
against  spontaneous  infection,  in  which  the  dose  of  infecting 
bacilli  is  always  very  small,  it  was  sufficient  to  inject  one  or 
at  the  most  two  small  vaccinating  doses.  The  serum  of  an 
animal  so  vaccinated  had  no  curative  power,  and  could  not 
cure  actual  disease;  but  it  was  reasonable  to  suppose  that 
by  multiplying  injections  and  by  increasing  the  doses  of  the 
vaccine,  sera  would  be  obtained  similar  in  curative  power  to 
antitoxic  sera  (diphtheria,  tetanus). 

It  was  also  thought  that  the  anaphylactic  complications 
were  the  very  obstacles  to  the  formation  of  large  quantities  of 
antibacterial  products,  and  thus  endeavors  were  made  to 
find  a  new  weapon  or  circuitous  road  to  overcome  this  obstacle 
or  to  avoid  it.  But  this  attempt  would  perhaps  not  have 
been  undertaken  with  so  much  alacrity,  had  not  the  accidents 


ANTI-ANAPHYLAXIS  OF  ANIMALS  147 

of  "  serum  disease"  in  children  to  be  fought  or  avoided.  This 
was  a  complication  which,  although  rare  and  often  very  mild, 
was  nevertheless  very  troublesome  in  cases  where  the  illness 
required  prolonged  treatment;  in  relapses,  or  also  when  it 
was  necessary  to  apply  serotherapy  to  the  same  patient, 
successively  in  different  diseases. 

In  this  research,  as  in  many  other  cases  where  the  logical 
deductions  from  a  general  and  well  established  law  offers  no 
guide,  chance  once  more  proved  itself  more  ingenious  than 
the  experimenters.  Considering  that  the  serum  which  causes 
an  anaphylactic  crisis  must  contain  a  poison,  Rosenau  and 
Anderson  in  America  and  Otto  in  Germany,  had  simul- 
taneously the  same  idea  of  endeavoring  to  immunize  guinea- 
pigs  against  this  poison  by  intraperitoneal  injections  of  large 
doses  (5.0  c.c.)  of  horse  serum,  at  regular  intervals  of  from 
five  to  six  days.  In  this  way  they  hoped  to  obtain  a  specific 
antidote  similar  to  antitoxin. 

It  will  be  conceded  that  this  idea  was  rather  peculiar: 
they  were  trying  to  obtain  an  anti-anaphylactic  product  by  a 
process  which,  as  was  already  well  known,  should  lead 
straight  to  anaphylaxis,  which  should  cause  a  poison,  not  a 
counter-poison  to  appear;  and  they  did  not  obtain  what  they 
were  seeking. 

But  a  well  performed  experiment  is  never  completely 
wasted.  Rosenau  and  Anderson  found  that  when  injections 
were  made  every  twelve  days,  there  were  often  anaphylactic 
accidents  at  the  time  of  the  second  injection,  whereas  when 
the  injections  were  made  every  five  days,  no  apparent  acci- 
dent occurred  at  the  third  injection,  that  is  twelve  days 
after  the  first  one;  that,  therefore,  the  intermediary  dose 
protected  the  animal  against  the  following  injection.  Soon 
after  this,  Besredka  and  Steinhardt,  who  at  first  followed 
the  errors  of  their  predecessors,  finally  discovered  that,  in 
order  to  avoid  an  anaphylactic  crisis  in  a  duly  anaphylactized 
animal,  it  was  sufficient  to  inject  a  very  small  dose  of  the 
product  a  few  minutes  before  the  shocking  dose. 

The  explanation  of  these  phenomena  is  very  simple.  It 
logically  follows  the  results  of  the  series  of  experiments 
quoted  above,  beginning  with  those  of  Hayem. 


148  THEORIES  CONCERNING  IMMUNITY 

It  is  not  the  serum,  the  blood  or  other  injected  heterol- 
ogous albumin  which  becomes  the  "poison"  at  the  time  of 
the  second  injection  since  it  is  always  the  same  substance 
which  is  injected,  without  having  undergone  any  kind  of 
change.  If  the  animal  becomes  ill  after  the  second  injection 
the  necessary  conclusion  is  that  he,  his  blood,  his  fluid  or  his 
tissues  were  modified  by  the  first  injection. 

In  what  does  this  modification  consist? 

As  already  seen  in  the  experiments  of  Pfeiflfer,  of  Krauss, 
and  of  J.  Bordet,  there  is  formed  in  the  blood  of  the  injected 
animal,  a  substance  which  precipitates  when  mixed  in  certain 
proportions  with  the  injected  albumin.  This  substance  was 
called  by  Krauss  "precipitin"  or  "precipitating  antibody." 

MECHANISM  OF  AN TI- ANAPHYLAXIS. 

We  have  seen  in  the  experiments  of  Hamburger  and  Moro 
that  the  antibody  appears  only  after  a  longer  or  shorter 
period  of  incubation,  and  that  this  appearance  coincides  with 
the  disappearance  of  the  antigen  from  the  organism  of  the 
treated  animal,  and  with  the  moment  when  the  treated 
animal  becomes  hypersensitive. 

We  saw  also,  in  Besredka's  experiments,  that  the  "  period 
of  incubation"  increases  in  length  with  the  dose  of  injected 
antigen,  which  means,  as  was  seen  in  the  previous  experiment, 
that  the  length  of  time  taken  by  the  antigen  to  disappear 
increases  with  the  quantity  of  the  injection. 

Therefore  assuming  that  for  a  certain  quantity  of  antigen 
the  incubation  period  is  twelve  days,  if  an  equal  dose  of 
antigen  is  injected  six  days  after  the  first  injection,  the  incu- 
bation period  will  be  prolonged,  and  the  animal  will  endure 
a  third  injection  on  the  twelfth  day  without  showing  any 
sign  of  trouble. 

Therein  lies  the  explanation  of  the  phenomenon  of  Rosenau 
and  Anderson  and  of  Otto. 

A  similar  explanat  on  applies  to  the  anti-anaphylaxis  of 
Besredka.  In  order  to  cause  an  anaphylactic  shock,  it  is 
necessary  to  inject  into  the  prepared  animal,  who  already 
is  in  a  state  of  anaphylaxis,  a  particular  dose  of  antigen. 


MECHANISM  OF  ANTI-ANAPHYLAXIS  149 

With  a  decreased  dose  the  shock  does  not  take  place,  which 
means  that  the  combination  of  the  antigen  with  the  antibody 
becomes  a  poison  only  if  the  two  substances  be  mixed  in 
certain  definite  proportions.  If  the  total  pathogenic  dose  is 
injected  in  non-pathogenic  fractions,  the  successively  formed 
combinations  never  become  a  "poison,"  and  it  is  found  that 
after  one,  or  after  a  series  of  these  preventive  injections,  the 
blood  of  the  animal  so  treated  no  longer  contains  precipitating 
antibodies.  It  is,  therefore,  to  use  Besredka's  expression, 
"  restored  anew,"  or,  to  be  more  exact,  it  begins  a  new  period 
of  incubation. 

The  reactions  obtained  by  the  "vaccinotherapy"  of  Al. 
Wright  should  be  classified  in  the  same  category.  This 
method  which  is  based  on  the  principles  of  Pasteur's  preven- 
tive vaccination,  in  reality  owes  its  success  to  anti-anaphy- 
lactic  reactions.  In  acute  infectious  diseases,  the  appearance 
of  symptoms  coincides  with  the  appearance  of  antibodies  in 
excess,  and  the  result  of  an  injection  of  killed  or  attenuated 
bacilli  is  to  neutralize  this  excess  antibod}^  At  the  same 
time  the  symptoms  of  the  disease  disappear. 

It  follows  of  necessity  that  the  pathological  manifestations 
of  disease  are  anaphylactic  in  nature,  and  that  the  result  of 
the  introduction  into  the  organism  of  a'  suitable  dose  of 
antigen  is  not  only  to  forestall  an  anaphylactic  crisis,  but 
also  to  cure  the  crises  as  they  develop. 

Attention  must  be  drawn  to  the  fact,  however,  that  this 
distinction  between  the  preventive  and  the  curative  anaphy- 
lactic actions  is  far  more  apparent  than  real.  The  course  of 
an  acute  infectious  disease  (such  as  typhoid  fever),  is  made 
up  in  reality  of  a  series  of  crises  succeeding  each  other  more 
or  less  rapidly  so  that  by  interfering  at  a  given  time,  one 
probably  does  not  affect  the  current  crisis,  but  prevents  the 
birth  of  the  crisis  which  would  otherwise  have  followed. 

Kichet's  experiments  were  thus  the  origin  of  a  series  of 
researches  undertaken,  in  addition  to  those  previously  men- 
tioned, by  many  scientists  of  all  countries,  von  Pirquet, 
Friedberger,  Schick,  Auer,  Ascoli,  Nicolle,  Doerr,  Russ, 
Bidl,  Eisenberg,  Vaughan,  Jobling,  Wheeler,  Novy,  de 
Kruif,  Levaditi,  Mutermilch,  and  others.  ...  It  would 
take  much  too  long  to  give  here  even  a  short  analysis. 


150  THEORIES  CONCERNING  IMMUNITY 

These  researches  may  be  said  to  have  brought  out  the 
following  general  principles: 

1.  Every  organism  capable  of  producing  an  antibody  in 
excess  by  the  action  of  a  given  antigen,  normally  contains  a 
small  quantity  of  this  antibody. 

2.  For  the  same  quantity  of  antigen,  the  amount  of  pre- 
cipitate formed  in  mixtures  of  antibody  with  its  antigen,  in 
vitro  and  in  vivo,  as  well  as  the  speed  of  this  formation,  is 
directly  proportional  to  the  quantity  of  antibody  (normal  or 
in  excess)  which  exists  in  the  blood  or  in  the  serum. 

3.  Every  anaphylactized  animal  can  be  vaccinated  in  a 
few  minutes  against  a  fatal  anaphylactic  shock,  by  the  pre- 
vious injection  of  a  non-pathogenic  dose  of  the  same  antigen; 
in  other  words,  a  pathogenic  anaphylactic  reaction  may  be 
prevented  by  a  previous  non-pathogenic  reaction. 

TACHYPHYLAXIS  OR  SKEPTOPHYLAXIS. 

Long  before  the  discovery  of  anti-anaphylaxis,  a  similar  if 
not  identical  phenomenon  was  known,  which  was  discovered 
and  confirmed  by  a  series  of  researches  concerning  the  direct 
toxic  action  of  peptones  and  of  certain  albuminoid  sub- 
stances such  as  extracts  of  organs,  eel  serum,  certain 
poisons,  etc. 

It  was  thus  observed  that  the  injection  into  a  vein  of  10 
to  20  eg.  of  a  peptone  solution  killed  a  dog  in  a  few  minutes. 
Beginning  with  tachycardia,  the  crisis  followed  with  dyspnea, 
sometimes  diarrhea,  and  ended  with  convulsions.  The  blood 
of  an  animal  so  treated  could  no  longer  coagulate.  Schmidt- 
Mulheim  was  the  first  to  observe  that  if  the  animal  survived 
a  first  peptone  injection,  its  blood  also  was  for  a  certain  time 
incapable  of  coagulation,  but  that  this  animal  would  endure 
a  second  dose  of  peptone,  even  stronger  than  the  first,  without 
any  modification  in  the  ability  of  the  blood  to  coagulate. 

This  phenomenon,  confirmed  by  Fano  (1882),  Grosjean 
(1892),  for  peptones  was  restudied  more  thoroughly  by  Roger 
and  Josue  (1896)  for  intestinal  extract.  Delezenne  demon- 
strated this  anticoagulating  action  for  the  extract  from 
crawfish,  eel  serum,  etc.    Delezenne  and  Bose  (1896-1898) 


TACHYPHYLAXIS  OR  SKEPTOPHYLAXIS       151 

found  that  peptone  protects  animals  against  fatal  injections 
of  colon  bacilli  and  streptococci,  in  short  that  certain  antigens 
protect  the  animal  against  the  pathogenic  action  of  other 
antigens  (living  bacilli  or  toxic  extracts),  and  therefore  that 
these  reactions  are  not  exclusively  specific.  Gley  and  Le  Bas 
(1897)  showed  at  the  same  time  that  a  non-pathogenic  dose 
of  peptone,  insufficient  to  prevent  the  coagulation  of  the 
injected  animal's  blood,  protects  this  animal  against  an 
ordinarily  fatal  dose,  and  that  this  immunity  is  very  rapidly 
acquired  in  a  few  minutes.  Hence  the  name  of  tachyphylaxis 
given  to  this  phenomenon. 

Schenk  (1889)  made  the  same  observation  for  placental 
extract,  and  Lambert,  Ancel  and  Bouin  later  (1910)  showed 
that  a  first  injection  of  a  non-pathogenic  dose  of  a  large 
number  of  extracts:  testicle,  thyroid,  liver,  brain,  muscle, 
kidney,  etc.,  immunized  in  a  few  minutes  (skeptophylaxis) 
against  the  injection  of  a  fatal  dose.  In  this  case  the  immun- 
ity was  not  an  exclusively  specific  one:  the  first  injection  of 
the  extract  from  one  organ  not  only  protected  against  a  fatal 
injection  of  the  same  extract,  but  also  against  the  extract 
from  any  other  organ. 

This  category  of  phenomena  should  also  include  passive 
anaphylaxis,  first  studied  by  M.  Nicolle,  Charles  Richet 
(1906-1907),  and  more  recently  (1910)  by  Novy  and  his 
collaborators.  This  research  showed  that  by  injecting  into  a 
normal  animal  first  a  small  amount  of  serum  from  an  anaphy- 
lactized  animal,  and  then,  shortly  afterward,  some  of  the 
original  antigen,  there  resulted  an  anaphylactic  crisis  exactly 
as  with  a  prepared  animal;  and  that  it  was  possible  to  prevent 
this  crisis  by  a  small  injection  of  the  same  antigen. 

An  anaphylactic  crisis  is  also  caused  by  injecting  into  a 
normal  animal  a  mixture  made  in  vitro  of  serum  from  an 
anaphylactized  animal  with  the  antigen. 

In  this  last  case,  the  mixture  therefore  of  serum  with 
antigen  acts  in  exactly  the  same  way  as  an  organ  extract,  a 
peptone,  or  as  other  directly  toxic  albuminoid  products,  so 
that  all  these  products  can  be  grouped  under  the  common 
name  of  anaphylatoxins. 


152  THEORIES  CONCERNING  IMMUNITY 

The  results  of  these  experiments  can  be  summarized  as 
follows : 

1.  Certain  albuminoid  products  as  such,  or  partially 
digested  (transformed  into  albumoses,  propeptones,  peptones) 
which  when  injected  in  non-pathogenic  doses  cause  the  ana- 
phylactic state  (active  sensitization),  are  able  to  cause  at 
first  injection  a  crisis  similar  in  every  way  to  anaphylactic 
shock,  when  a  strong  dose  is  injected  into  the  veins. 

2.  The  injection  of  a  non-pathogenic  dose  of  these  prod- 
ucts immunize  in  a  few  minutes  against  a  fatal  dose,  exactly 
as  in  the  anti-anaphylaxis  of  Steinhardt  and  Besredka. 

We  can  conclude  therefore  that : 

The  crises  which  follow  the  second  injection  of  an  antigen, 
and  the  first  injection  of  an  anaphylatoxin  are  caused  by 
reactions  of  the  same  kind;  or,  in  other  words,  the  normal 
organism  is  in  the  same  state  of  sensitiveness  to  anaphyla- 
toxins  as  a  prepared  organism  is  to  a  second  dose  of  the 
specific  antigen. 

PHYSIOLOGICAL    AND   PHYSICOCHEMICAL    CAUSES    OF 

THE  FORMATION  OF  ANTIBODIES  IN  EXCESS 

BY  ANTIGENIC  ACTION. 

We  know  now^  hoio  and  in  what  circumstances  an  animal 
becomes  anaphylactized;  there  remains  to  explain  why 
anaphylaxis  exists,  and  in  particular: 

1.  Why  heterologous  albumins  and  biologic  colloids  as 
a  class  are  antigens. 

2.  Why  the  process  of  immunization  by  albuminoid 
antigens  is  complicated  by  pathologic  manifestations. 

3.  Why  diphtheria  and  tetanus  toxins  are  exceptions  to 
this  general  rule. 

4.  Finally,  why  crystalloids  are  not  antigens. 

The  result  of  our  summary  of  the  above  researches  as  a 
whole  is  that  the  process  of  immunization  consists  in  the 
production  by  the  organism  of  an  antibody  which  is  found  in 
excess  in  the  blood  or  in  the  tissues  of  immunized  animals. 

This  antibody  neutrahzes  in  all  cases  the  actual  patho- 
genic principle  of  the  infecting  agent:  an  organism  vaccinated 


CAUSES  OF  FORMATION  OF  ANTIBODIES         153 

against  Eberth's  bacillis  becomes  better  able  to  resist  typhoid 
infection.  Where  the  bacillus  acts  solely  by  its  albumin 
(cholera,  typhoid  fever),  or  simultaneously  by  its  albumin 
and  its  toxin  (certain  pneumonias,  dysenteries,  meningitides) , 
the  neutralization  of  the  albumin-antigen  by  the  antibody  in 
excess  causes  a  pathological  reaction. 

In  such  cases,  the  pathological  manifestations  which 
characterize  disease  are  caused  not  by  the  direct  action  of  a 
bacterial  poison,  but  by  a  reaction  resulting  from  the  com- 
bination of  antigen  with  antibody. 

It  is  easy  today,  by  carefully  analyzing  these  experimental 
facts  to  understand  the  causes  of  the  confusions,  of  the 
apparent  contradictions  and  of  the  errors  in  interpretation 
of  certain  experiments:  The  process  of  immunity  is  never  a 
simple  reaction,  because  biological  antigens  are  never  chemically 
simple  substances.  The  simplest  of  all,  a  diphtheria  or 
tetanus  toxin,  is  a  mixture  of  a  large  number  of  complex 
compounds  arising  from  the  culture  fluid  on  the  one  hand,  and 
from  the  bacillus  on  the  other.  The  bacillus  body  is  very 
probably  composed  of  several  kinds  of  albumins  and  of  sub- 
stances derived  from  these  albumins,  which,  when  dissociated 
in  the  infected  organism,  may  each  on  its  own  account  be 
anaphylactic  or  "  antigenic"  and  may  cause  different  chemical, 
physiological  and  pathological,  direct  or  secondary,  reactions. 
Some  produce  antitoxins,  others  anaphylactic  antibodies, 
still  others  produce  antibodies  which  are  both  antitoxic  or 
anti-infectious  and  anaphylactic. 

With  toxins  or  very  virulent  bacilli,  certain  directly  patho- 
genic principles  are  so  predominant  that  the  reactions  caused 
by  the  other  antigens  are  practically  negligible;  in  many 
other  cases  (syphilis,  malaria,  trypanosomiasis,  typhoid 
fever,  etc.),  the  contrary  has  been  found:  In  the  case  of 
albumins  of  only  a  slightly  toxic  nature  the  anaphylactic 
reactions  are  predominant. 

We  can  consider  as  the  two  extremes  in  this  order  of  ideas : 
on  the  one  hand  the  filtered  broth  cultures  of  tetanus  or 
diphtheria  (toxin)  directly  and  nearly  exclusively  toxic  with- 
out anaphylaxis;  on  the  other  hand  a  heterologous  serum  or 
white  of  egg  exclusively  anaphylactizing;  and  between  these 


154  THEORIES  CONCERNING  IMMUNITY 

two  extremes  we  shall  find  all  the  intermediaries,  that  is 
immunity  complicated  by  more  or  less  anaphylaxis. 

We  now  have  sufficient  basis  to  understand  the  cause  of 
the  reactions  from  antibodies  in  normal  quantity  or  in  excess : 

All  antigens  are  heterologous  colloids;  colloids  can  neither 
be  assimilated  nor  eliminated  without  having  first  been 
changed  into  salts  or  into  crystalloids.^ 

A  rabbit  can  readily  absorb  horse  serum  by  mouth  without 
ever  becoming  ill.  The  reason  for  this  is  that  the  serum  thus 
absorbed  penetrates  into  the  blood  only  after  having  been 
digested. 

On  the  other  hand  we  know  (Hamburger  and  Moro)  that 
horse  serum  injected  into  the  blood  of  a  rabbit  always  finally 
disappears  and  we  know  that  it  is  not  eliminated  as  serum. 

The  chemical  study  of  these  phenomena  is  far  from  com- 
plete, but  judging  by  what  we  do  know,  we  can  well  assume 
that  serum  injected  into  a  vein  undergoes  the  same  trans- 
formations in  the  interior  of  the  organism  as  in  the  digestive 
tract,  in  other  words,  that  it  is  digested.  This  digestion 
occurs  in  organs  which  normally  are  not  adapted  to  this 
function.  They  may  be  induced  to  so  act  by  repeated  injec- 
tions of  serum,  and  then  produce  antibodies  in  excess  which 
contribute  toward  this  digestion,  as  characterized  by  the 
precipitation  of  horse  serum  in  vitro  and  in  vivo. 

The  antibodies  found  in  sera  of  immunized  animals  do 
not  digest  their  respective  antigens  in  vitro,  therefore,  they 
do  not  contain  all  the  ferments  necessary  for  complete 
digestion. 

Such  antibodies  as  we  have  so  far  been  able  to  obtain 
in  sera  must  be  considered  as  substances  which  contribute 
to  this  digestion,  which  prepare  for  it  by  fixing  themselves 
to  the  antigens,  and  which  give  in  vitro  only  the  first  phase 
of  a  series  of  reactions  which,  effected  in  the  organism,  ter- 
minate by  the  total  disintegration  of  the  albumins. 


*  Certain  crystalloids,  such  as  antipyrin,  quinine,  some  mercury  salts, 
become  indirect  antigens  in  the  organism,  either  by  forming  colloidal  com- 
pounds with  certain  substances  of  the  organism,  or  by  transforming  certain 
substances  of  the  organism,  which  then  become  antigens  (indirect  anaphylaxis 
of  Charles  Richet). 


CAUSES  OF  FORMATION  OF  ANTIBODIES        155 

The  causes  of  the  differences  in  the  reactions  caused  in 
the  organism  by  the  different  antigens— immunity  without 
anaphylactic  shock,  immunity  accompanied  by  anaphy- 
lactic shock,  or  anaphylaxis  alone  as  well  as  the  action  of  the 
anaphylatoxins  must  be  looked  for,  in  the  different  stages 
of  albumin  disintegration  on  the  one  hand,  in  the  nature  and 
physicochemical  or  physiological  properties  of  antibodies 
on  the  other. 

All  that  we  know  today  is  that  the  antigens  which  cause 
the  formation  of  precipitating  antibodies  and  therefore  pre- 
dispose the  organism  to  anaphylactic  shock,  have  a  total  of 
properties  characteristic  of  the  albumins  (animal  fluids  and 
formed  elenients,  vegetable  albumins,  bacterial  bodies); 
whereas  antibodies  produced  by  non-albuminous  antigens 
(toxins)  do  not  precipitate  antigens  and  do  not  predispose 
to  anaphylactic  shock. 

It  has  so  far  been  impossible  to  obtain  an  antibody  in  a 
pure  state  and  to  separate  from  it  the  albuminoid  substances 
of  the  serum  which  are  not  antibodies  (and  these  always 
exist,  as  can  easily  be  recognized  by  analyzing  the  liquid 
which  floats  above  the  precipitate  formed  in  a  mixture  of  a 
serum-antibody  with  its  antigen) ;  nevertheless,  since  there 
are  albumin-antigens  and  peptone-antigens  or  polypeptides, 
it  can  be  assumed  that  the  differences  between  antibodies  are 
of  the  same  order  as  the  differences  between  pepsin  and 
kinase  or  erepsin. 

Pepsin  transforms  liquid  albumin  into  peptones  by  first 
precipitating  them;  kinase  and  erepsin  transform  peptones 
into  amino-acids  without  precipitation. 

We  may  therefore  conclude  that : 

1 .  The  cause  of  the  production  of  antibodies  in  excess,  and 
at  the  same  time,  of  the  state  of  immunity-anaphylaxis,  is 
the  obligation  on  the  part  of  the  organism  to  digest,  by  means 
of  its  cells,  the  antigens  which  have  penetrated  to  its  interior. 

2.  The  excess  antibody  found  in  the  serum  and  in  the 
fluids  is  a  substance  which  contributes  to  this  digestion. 

3.  Salts  and  crystalloids  are  not  antigens  because  they  are 
assimilated  or  eliminated  directly  without  previous  digestion 
or  disintegration. 


156  THEORIES  CONCERNING  IMMUNITY 

IMMEDIATE    AND    SECONDARY    RESULTS    OF    THE 
CONDITION  OF  IMMUNITY- ANAPHYLAXIS. 

An  organism  which  has  been  immunized  or  sensitized  by  an 
antigen  is  no  longer  a  normal  organism,  and  it  will  remain 
abnormal  as  long  as  it  will  produce  antibodies  in  excess. 

The  principal  object  of  research  concerning  active  immun- 
ity up  to  the  present,  was  to  obtain  an  immediate  result:  in 
immunity  an  accrued  resistance  against  spontaneous  or 
experimental  infection;  in  anaphylaxis,  a  more  or  less  severe 
rapid  crisis  or  vaccination  against  this  crisis. 

It  was  known  that  although  in  certain  cases  (tuberculosis, 
syphilis)  immunity  and  anaphylaxis  ceased  to  exist  during 
the  period  of  infection  in  the  large  majority  of  cases,  immun- 
ity and  anaphylaxis  are  more  or  less  lasting  chronic  states; 
and  we  have  seen  above  (Arthus'  phenomenon)  that  experi- 
mental intensive  immunization  of  animals  ends  most  often 
in  chronic  morbid  states. 

When  horse  serum  in  very  small  doses  (0.01  c.c.  to  0.1 
c.c.)  is  injected  into  the  vein  of  a  rabbit,  and  when  this 
injection  is  repeated  daily,  or  even  two  or  three  times  daily 
for  several  weeks,  no  crisis  of  acute  anaphylaxis  is  ever 
observed,  although  the  rabbit  serum  after  the  first  fortnight 
becomes  a  strong  precipitant  of  horse  serum.  The  immunity 
of  the  rabbit  against  these  injections  is  explained  by  the 
action  of  the  small  doses  which  are  vaccinating  one  for  the 
other. 

If,  after  this  series  of  injections  w^hich  occasioned  no  note- 
worthy incident,  the  rabbits  are  kept  at  rest  and  under 
observation,  it  is  found  two  or  three  months  later  that,  out 
of  a  dozen  animals  so  treated,  one  or  two  will  show  nerve 
palsies,  others  dermatoses  with  alopecia,  others  rheumatism ; 
and  even  if  no  accidental  infectious  disease  interferes  with 
the  experiment,  at  the  end  of  a  year  only  one  or  two  animals 
will  remain  alive.  All  the  others  will  have  been  affected  by 
more  or  less  well  characterized  chronic  diseases,  and  will  have 
succumbed  to  cachexia. 

Similar  phenomena  are  observed  with  all  horses  that  have 
been  intensively  immunized  for  the  production  of  antitoxic 
or  antibacterial  sera. 


RESULTS  OF  IMMUNITY-ANAPHYLAXIS  157 

All  these  animals  at  first  become  less  active  and  vigorous 
and  often  succumb  to  internal  hemorrhages  caused  by  a 
rupture  of  the  liver.  At  autopsy  in  a  certain  number  of 
immune  horses  A.  Petit  and  G.  Loiseau^  found  the  following 
lesions:  "marked  changes  in  the  hemolymphatic  organs, 
which  are  the  seat  of  definite  hyperplasia  (spleen  and  bone 
marrow);  the  endocrin  glands  show  evident  signs  of  hyper- 
secretion; the  liver  and  especially  kidney  show  quite  definite 
lesions." 

The  results  of  repeated  injections  of  foreign  proteins  into 
the  tissues  and  organs  of  guinea-pigs  have  recently  been 
studied  by  W.  T.  Longcope^  and  by  T.  Harris  Boughton^  who 
found  degenerative  lesions  of  the  small  arteries  in  nearly  all 
organs  excepting  the  lungs:  The  lesion  begins  with  edema 
of  the  endothelium,  followed  by  granular  degeneration  and 
vacuolization  of  the  cells  with  rupture  of  the  intima.  The 
nuclei  may  disappear  (be  expelled).  Then  comes  a  stage  of 
regeneration  with  increase  in  the  number  of  endothelial 
nuclei.  The  edema  reaches  the  internal  elastic  layer  which 
may  rupture.  This  swelling  and  undermining  may  extend 
to  the  whole  of  the  middle  coat.  There  is  no  connective- 
tissue  proliferation.  The  more  serious  lesions  are  found  in 
the  liver  in  the  animals  killed  by  shock  or  which  died  during 
the  week  following  the  last  injection  of  protein.  LongcopC 
also  has  described  very  important  and  interesting  lesions 
consisting  of  round-cell  infiltration,  degeneration  and  finally 
necrosis  with  scar  formation  especially  in  the  heart,  kidneys 
and  liver  of  rabbits  repeatedly  injected  with  egg-white. 

In  order  to  understand  the  nature  and  the  pathogenicity 
of  the  morbid  manifestations  which  an  organism  so  treated 
may  undergo,  two  phenomena  must  be  taken  into  account: 

1.  The  presence  of  the  antibody  in  the  blood  and  tissues. 

2.  The  production  of  this  antibody  in  excess  by  the  cells 
of  certain  organs. 

1  Bull.  Biolog.  Soc,  May  26,  1908,  p.  869. 

2  The  Relationship  of  Chronic  Protein  Intoxication  in  Animals  to  Ana- 
phylaxis, Jour.  Exper.  Med.,  1915,  xxii,  793. 

^  Vascular    Lesions   in    Chronic    Intoxication  by  Proteins,  Tr.  Chicago 
Pathol.  Soc,  April,  1917,  x,  156-157. 
*  Loc.  cit. 


158  THEORIES  CONCERNING  IMMUNITY 

The  presence  of  an  excess  of  antibody  in  the  blood  exposes 
the  organism  to  a  more  or  less  violent  anaphylactic  shock 
whenever  a  new  dose  of  antigen  comes  in  contact  with  it. 

Symptoms  are  explained  by  the  formation  of  a  precipitate 
which  obstructs  the  capillaries  and  causes,  in  consequence,  a 
sudden  break  in  the  nutritive  equilibrium  in  the  cells  of 
various  tissues,  and  especially  in  the  cells  of  the  nervous 
system. 

The  production  of  excess  antibody  results  in  hypertrophy 
and  in  lesions  of  nearly  all  the  organs  the  reactions  of  which 
maintain  the  normal  functions  of  the  organism. 

We  saw  above  (A.  Petit  and  G.  Loiseau)  that  horses 
immunized  against  toxins  or  bacterial  cultures  show  radical 
changes  and  lesions  in  liver,  kidney,  spleen,  endocrin  glands, 
hemol>Tnphatic  glands.  Similar  lesions  are  found  in  rabbits 
injected  with  horse  serum. 

These  lesions  of  necessity  depress  the  functions  of  these 
organs;  and  it  is  solely  in  these  more  or  less  pronounced 
depressions  that  the  direct  or  indirect  causes  of  the  lesions 
of  skin,  digestive  apparatus,  joints,  lungs  (asthma,  emphy- 
sema), nervous  troubles  (neurasthenia,  cachexia,  etc.)  are 
to  be  found. 

We  are  thus  led  quite  naturally  to  assume  that  in  all  cases 
of  chronic  disease  of  unknown  origin,  the  primary  cause  of 
the  lesions  and  of  the  apparent  symptoms  must  be  looked  for 
in  the  anaphylactic  state  brought  about  by  the  antigen. 

Might  it  be  possible  to  attribute  the  lesions  observed  at 
autopsy  to  a  direct  toxic  action  of  culture  fluid  ? 

This  is  hardly  probable  since  immediately  after  the  first 
few  small  non-pathogenic  injections,  there  is  found  in  the 
blood  of  animals  so  treated  a  much  greater  quantity  of  anti- 
bodies than  is  needed  to  neutralize  the  injected  doses  of 
bacterial  poison.  There  is  even  less  probability  in  the  case 
of  rabbits  injected  with  horse  serum,  which  properly  speak- 
ing, is  not  a  poison. 

A  harmful  action  is  certainly  present  since  the  organism 
sooner  or  later  becomes  ill.  There  is  a  breakdown  of  the 
physicochemical  and  therefore  vital  equilibrium  of  the 
affected  cell;  but  this  breakdown  of  equilibrium  results  not 


ORIGIN  OF  CHRONIC  NON-CONTAGIOUS  DISEASES    159 

from  the  direct  combination  of  a  foreign  substance  (poison) 
with  the  contents  of  the  cell,  but  ,from  the  overproduction 
of  a  substance  (antibody)  which  normally  is  produced  by  the 
cell  in  small  quantities  only. 

Briefly :  The  overburdening  of  the  cells  entrusted  with  the 
production  of  antibodies  causes  the  hypertrophy,  the  lesion 
and  the  insufficient  functioning  of  the  organ;  and,  conse- 
quently, the  appearance  of  chronic  disturbances. 


ORIGIN  OF  CHRONIC  NON-CONTAGIOUS  DISEASES. 

The  lesions  and  the  pathological  states  observed  in  animals 
intensively  immunized  or  sensitized  are  caused  by  conditions 
which  in  nature  occur  only  very  rarely.  They  are  sometimes 
observed  in  chronic  infectious  diseases  of  slow  and  very  long 
evolution,  particularly  in  tuberculosis,  syphilis,  malaria,  the 
trypanosomiases,  and  it  is  impossible  in  these  cases  not  to 
correlate  the  causes  and  results  of  the  succession  of  crises, 
alternating  with  more  or  less  long  abatements  in  the  chronic 
infections,  on  the  one  hand,  with  the  rep>eated  injections  of 
living  or  dead  antigens,  on  the  other. 

Preventive  vaccinations  as  practised  on  man  and  domestic 
animals,  usually  do  not  lead  to  unpleasant  consequences, 
because  the  doses  are  small  and  the  injections  not  numerous. 
The  immunity-anaphylaxis  acquired  by  vaccinations  is, 
however,  in  most  cases  of  short  duration. 

Acute  infectious  diseases  usually  leave  the  recovered 
organism  with  a  lasting  immunity-anaphylaxis;  but  it  has  so 
far  been  impossible  to  establish  with  accuracy  the  relations 
which  may  exist,  for  instance,  between  an  eruptive  or  typhoid 
fever  contracted  during  childhood,  with  a  dermatosis  or 
arthralgia  appearing  in  mature  age.  It  is  hardly  possible  to 
acquire  accurate  knowledge  in  these  cases  by  experiment, 
because  in  order  for  the  experiment  to  correspond  exactly 
to  any  particular  question,  it  would  be  necessary  to  consider 
entirely  new  and  perfect  organisms,  which  in  all  probability 
do  not  exist.  On  account  of  heredity  and  of  the  conditions 
of  individual  evolution  each  organism  finds  itself  in  a  different 


160  THEORIES  CONCERNING  IMMUNITY 

state  of  immunity-anaphylaxis ;  and  even  if  these  differences 
are  not  usually  sufficiently  pronounced  to  interfere  with 
ordinary  biological  experiments,  they  do  exert  a  decisive 
influence  on  secondary  and  distant  reactions. 

To  these  differences  of  ''diathesis"  must  be  attributed  the 
different  pathologic  manifestations  observed  in  the  case  of 
rabbits  injected  with  horse  serum.  For  the  same  reason 
injections  of  arsenobenzene  will  cause  gastro-intestinal  dis- 
turbances in  certain  individuals,  dermatoses  or  arthritides 
or  nervous  disturbances  in  still  others  or  perhaps  all  these 
symptoms  at  the  same  time;  while  in  the  majority  of  cases, 
there  will  be  no  apparent  reaction. 

It  is  solely  by  the  state  of  previously  acquired  immunity- 
anaphylaxis  that  one  can  explain  the  idiosyncrasies,  predis- 
positions or  hypersensitiveness  of  individuals  to  foreign 
proteins  of  all  kinds,  to  drugs,  to  certain  smells,  to  changes 
in  temperature  and  to  emotions.  So  that  when  one  meets 
these  same  morbid  states  manifesting  themselves  chronically 
without  any  apparent  immediate  cause,  the  idea  forces 
itself  of  its  own  accord  that  these  diseases  can  have  but  one 
origin,  a  preexisting  state  of  immunity-anaphylaxis. 

In  order,  therefore,  to  find  a  biological  method  of  treating 
these  diseases  in  conformity  with  the  conception  of  the 
specificity  of  ''sensitizing"  and  "shocking"  antigens,  it  is 
necessary,  above  all,  to  search  for  the  antigen  which  is  the 
primary  cause  of  the  disease,  and  which  may  be  different  in 
each  particular  case. 

That  a  definite  susceptibility  to  foreign  proteins  existing 
in  the  form  of  dust  and  with  which  the  patient  comes  in 
contact  through  the  respiratory  tract,  as  well  as  in  the  form 
of  food  which  is  ingested,  jn&y  be  responsible  for  a  certain 
number  of  chronic  states  has  recently  been  discovered. 

The  literature  contains  many  reports  of  these  cases  and  such 
diseases  as  hay  fever,  asthma,  urticaria  and  eczema  should 
always  be  studied  with  the  possibility  of  such  a  foreign  pro- 
tein sensitiveness  in  mind.    The  studies  of  Goodale,^  Long- 


^  Diagnosis  and  Management  of  Vasomotor  Disturbances  of  the  Upper 
Air  Passage,  British  Med.  and  Surg.  Jour.,  1916,  clxxv,  181. 


ORIGIN  OF  CHRONIC  NON-CONTAGIOUS  DISEASES    161 

cope/  Walker,^  Schloss,^  Cooke^  and  many  others  have 
brought  out  the  fact  that  this  hypersensitiveness  depends 
upon  an  inherited  tendency,  the  nature  of  which  is  unknown, 
that  it  can  be  demonstrated  by  applying  some  of  the  protein 
to  a  scratch  in  the  patient's  skin  and  observing  the  urticarial 
wheal  which  occurs  locally  within  ten  minutes  and  finally 
that  this  hypersensitiveness  and  the  clinical  conditions 
depending  on  it  can  be  relieved  by  treatment  either  by 
removal  of  the  offending  protein  or  vaccination  with  an 
extract  of  it.  In  some  of  these  cases  the  hypersensitiveness 
is  to  bacteria  or  their  products. 

The  local  reaction  as  well  as  the  clinical  conditions  depend 
upon  an  excess  of  antibodies  in  the  cells  which  at  once  com- 
bine with  the  foreign  protein  by  virtue  of  their  extraordinary 
affinity  for  it  and  form  a  product  which  is  insoluble  and  poi- 
sonous for  the  cell  and  for  the  organism.  Briefly,  the  method 
of  treatment  in  chronic  diseases  is  "vaccinotherapy"  which 
has  been  so  successfully  studied  and  applied  by  Al.  Wright 
in  the  treatment  of  certain  acute  infectious  diseases;  and  it 
is  in  this  direction  that  experiments  were  undertaken. 

1  The  Susceptibility  of  Man  to  Foreign  Proteins,  Am.  Jour.  Med.  Sc, 
1916,  No.  5,  clii,  625. 

2  Studies  in  Asthma,  Jour.  Med.  Research,  1917. 

3  Allergy  in  Infants,  Am.  Jour.  Dis.  of  Children,  1920,  xix,  433. 
^  Human  Sensitization,  Jour.  Immunology,  1916,  i,  3. 


11 


CHAPTER  XL 

PRINCIPLES   OF   THE   ANTI-ANAPHYLACTIC 

TREATMENT  OF  CHRONIC  DISEASES 

BY  ENTERO-ANTIGENS. 

From  Metchnikoff's  work  on  intestinal  flora  it  could  be 
deduced  that  the  digestive  tract,  and  especially  the  large 
intestine  must  be  considered  as  the  principal  source  of  all 
kinds  of  infections  and  of  chronic  intoxications.  Metchnikoff 
thought  that  these  intoxications  were  due  to  the  develop- 
ment and  to  the  secretions  of  certain  bacilli,  and  that  by 
modifying  the  reaction  of  the  medium  in  which  they  lived,  it 
would  be  possible  to  prevent  their  multiplication.  He 
endeavored  to  obtain  this  result  by  causing  in  the  intestine 
an  acid  reaction  by  means  of  the  bacteria  of  curdled  milk. 

Allen,!  S.  Marbais,^  A.  Berthelot  and  D.  Bertrand^  and 
others  tried  to  obtain  the  same  result,  i.  e.,  the  destruction 
of  poisonous  intestinal  bacilli,  by  bacteriotherapy  based  on 
the  "vaccinotherapy"  of  Al.  Wright. 

Metchnikoff's  idea  of  looking  for  the  origin  of  gastro- 
intestinal disturbances  in  the  normal  intestinal  flora  is  prob- 
ably very  sound,  and  the  treatment  of  such  troubles  by  the 
bacteria  of  curdled  milk  or  by  bacteriotherapy  has  often 
given  very  good  results;  but  it  was  found,  however,  at  the 
same  time,  that  while  the  disease  was  cured,  the  intestinal 
flora  was  not  appreciably  changed. 

Treatments  by  Bacillus  bulgaricus  or  by  intestinal  bacilli 
were  therefore  efficient,  although  the  mode  of  action  was  not 
in  accordance  with  the  theory. 

1  Vaccinotherapy,  Levis,  London. 

2  Bull,  de  la  Soc.  de  Biol.,  February  20,  1915,  p.  66. 

'  Vaccinotherapy  in  Chronic  Enteritis,  La  Presse  med.,  1917,  Nos.  23 
and  44, 


ANTI-ANAPHYLACTIC   TREATMENT  OF  DISEASES     163 

Then  again,  we  must  not  lose  sight  of  the  fact  that  the 
intestinal  contents  are  not  solely  composed  of  bacteria,  that 
they  always  contain  more  or  less  digested  albuminous  matter, 
and  that  the  congested  intestinal  mucous  membrane  may 
allow  this  matter  to  pass  into  the  blood. 

We  know  that  any  heterologous  albuminous  substance 
which,  undigested  or  incompletely  digested,  that  is,  in  the 
form  of  albumose,  peptone  or  polypeptid,  has  penetrated 
into  the  blood,  will  behave  as  an  antigen,  and  we  know  that 
any  ordinary  occurrence,  even  a  slight  emotion,  can  make 
the  intestinal  mucous  membrane  permeable  to  these  antigens, 
as  well  as  to  bacterial  antigens. 

An  anaphylactic  state,  as  well  as  the  disturbances  resulting 
from  it,  can  thus  be  caused  just  as  well  by  incompletely 
digested  alimentary  substances,  as  by  intestinal  bacteria  or 
their  secretions;  but  as  it  is  easy  to  determine  and  to  prove 
that  the  intestinal  flora  and  the  digestion  of  a  normal  man 
do  not  differ  from  those  of  a  man  affected  by  psoriasis  or 
suffering  from  emphysema,  the  conclusion  is  necessary  that 
the  causes  of  these  diseases  must  be  looked  for,  not  in  the 
nature  of  the  bacteria  living  in  the  intestine,  nor  in  the  nature 
of  the  albuminoid  substances  on  which  the  organism  feeds, 
but  solely  in  the  method  by  which  it  digests  and  assimilates 
both  bacteria  and  albumin. 

It  often  happens  that  of  several  thousand  individuals 
living  in  the  same  surroundings  and  under  the  same  condi- 
tions, only  a  few  became  ill  with  typhoid  fever  or  chdlera, 
and  one  wonders  why  the  remainder  escape  infection :  Why 
horses,  rabbits,  guinea-pigs,  are  not  infected  by  the  ingestion 
of  the  bacilli  of  these  diseases,  which  are  pathogenic  for 
these  animals,  when  injected  into  the  peritoneum  or  into  the 
blood. 

In  the  case  of  man,  we  may  assume  a  previous  spontaneous 
immunization  in  certain  cases,  but  in  animals,  this  is  very 
improbable.  The  only  plausible  answer  to  these  questions 
is  that  the  large  majority  of  individuals  who  escape  infection, 
and  all  animals  who  are  never  spontaneously  infected,  are 
refractory  to  these  diseases. 

And  why  are  they  refractory? 


164     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

Simply  because  they  either  digest  and  completely  destroy 
these  bacilli,  or  they  attack  them  not  at  all,  in  short,  because 
these  bacilli  or  their  secretions  do  not  penetrate  into  the 
blood  as  incompletely  digested  albumins  or  colloids. 

Pathogenic  bacteria  differ  from  those  which  are  not  patho- 
genic principally  because  the  first  can  live  and  multiply  in 
blood  and  living  tissue,  while  the  others  are  destroyed  by 
phagocytes  or  by  proteolysis  before  having  had  the  time  to 
multiply;  yet  both  the  first  and  the  second  will  by  their 
albumins  cause  anaphylactic  states. 

Bacteria  of  the  intestinal  flora  are  thus  not  pathogenic, 
properly  speaking,  because  they  cannot  multiply  in  the 
blood  or  in  the  tissues,  but  their  albumins  may  penetrate  into 
the  blood  through  a  congestion  of  the  intestinal  mucosa  and 
cause  an  anaphylactic  state  in  the  same  way  as  any  other 
heterologous  albumin. 

From  the  whole  of  these  conjectures  and  of  the  precise 
facts  determined  experimentally,  one  may  therefore  conclude 
that : 

1.  Chronic  disturbances  of  nutrition  which  manifest 
themselves  by  different  symptoms  according  to  the  affected 
organs  or  tissues,  have  for  their  common  cause  a  state  of 
anaphylaxis. 

2.  This  state  of  anaphylaxis  arises  from  the  introduction 
into  the  blood  of  bacterial  or  of  alimentary  albuminoid 
substances. 

3.  The  resulting  illnesses  may  successfully  be  treated  by 
antigens  taken  from  the  normal  intestinal  flora.  This  treat- 
ment is  neither  anti-infectious  nor  antibacterial  but  solely 
anti-anaphylactic. 

Inspired  by  these  considerations  we  undertook  at  random 
a  series  of  attempts  at  anti-anaphylactic  treatment,  at  first 
of  some  dermatoses,  and  later  of  all  kinds  of  other  chronic 
affections. 

I.  CASE  REPORTS. 

A.  Deim&toses.— Observation  L— Indeterminate  Dermatitis. 
— M.  F.  W.,  aged  forty-five  years.  For  four  years  oozing 
red  plaques  varying  in  size  from  a  pea  to  a  fifty-cent  piece 


CASE   REPORTS  165 

all  over  the  body,  and  particularly  on  the  legs.  Insufferable 
itching.  Sleepless  nights,  emaciation.  General  condition 
bad,  attributed ,  to  insomnia.  Transient  gastro-intestinal 
disturbances. 

The  patient  has  consulted  several  specialists,  and  has  tried 
several  external  treatments  and  changes  in  diet,  without 
lasting  success. 

Examination  of  the  Intestinal  Flora.— ^o  account  was 
taken  except  of  germs  which  grew  in  twenty-four  hours' 
incubation  on  ordinary  gelatin  slants  (meat-broth,  pep- 
tone). 

Found.— Colon  bacilli  90  per  cent.,  enterococci  5  per  cent., 
indeterminate  diplococci  3  to  4  per  cent.,  very  small  strepto- 
cocci 1  to  2  per  cent. 

Preparation  to  he  Injected.— A\l  the  germs  were  mixed  in 
0.7  per  cent,  salt  solution  in  the  proportions  in  which  they 
grew  on  the  gelatin.  The  mixture  was  distributed  in  sealed 
ampoules,  sterilized  by  heating  to  70°  C.  for  an  hour. 

Each  ampoule  contained  about  1  c.c.  of  liquid  with  about 
0.02  mg.  of  bacterial  matter  dried  at  140°  to  constant 
weight. 

Treatment.— First  Series  of  Injections.— First  injection  at 
2  P.M.,  1  c.c.  into  the  muscular  tissue  of  the  arm.  Slight  chills 
three  or  four  hours  after  the  injection.  No  itching  at  night, 
good  sleep.  Next  day,  slight  general  fatigue,  slight  pain  and 
redness  at  the  point  of  inoculation. 

Second  injection,  twenty-four  hours  after  the  first,  0.5  c.c. 
followed  every  day  for  a  week  by  injections,  increasing  the 
doses  from  0.1  c.c.  to  the  maximum  of  1.0  c.c. 

The  patient  no  longer  suffers  from  itching,  the  plaques 
have  faded  and  are  not  so  moist. 

No  treatment  for  the  next  month. 

At  the  end  of  the  month,  the  plaques  are  clearly  on  the 
road  to  recovery.  There  is  no  more  itching,  sleep  is  good, 
general  condition  much  improved. 

New  Examination  of  the  Intestinal  Flora.— The  same  germs 
are  found  in  the  same  proportions. 

Serum  Diagnosis.— The  serum  of  the  patient  does  not 
agglutinate  any  of  the  germs  in  a  1  to  40  dilution. 


166     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

Second  series  of  injections  under  the  same  conditions  as 
the  first,  with  this  difference  that  at  the  beginning  the  dose 
was  very  small,  0.1  c.c. 

Results.— At  the  end  of  the  second  series  of  injections,  the 
plaques  have  completely  disappeared. 

For  five  years  the  patient  has  been  in  very  good  health, 
from  every  point  of  view. 

Observation  2.— Urticaria  with  Phlyctenules.— M..  L.,  aged 
forty-two  years.  General  condition  fair.  Declared  "fit"  for 
active  service  at  the  beginning  of  the  war.  Discharged  after 
three  months  for  incurable  skin  disease. 

The  patient  has  lived  for  fourteen  years  in  central  Africa, 
where  beginning  with  the  first  year  of  his  residence  there,  he 
contracted  a  skin  disease  characterized  by  the  appearance 
on  the  whole  surface  of  the  body,  but  especially  on  the  back, 
of  small,  red  phlyctenules  with  a  small  yellowish  center. 
This  center  exuded  a  small  amount  of  pinkish  liquid  which 
dried,  leaving  a  red  crust.  Insufferable  itching  after  the  least 
fatigue  together  with  sweating. 

The  patient  has  consulted  many  dermatologists,  and  has 
followed  without  success  all  the  treatments  recommended, 
among  others,  he  has  received  several  injections  of  his  own 
serum.  One  of  the  dermatologists  he  consulted  told  him 
that  his  dermatosis  was  very  similar  to  scabies. 

The  bacteriologic  examination  of  the  patient's  stools  gave 
approximately  the  same  results  as  in  the  preceding  case,  and 
the  same  treatment  was  applied  with  exactly  the  same  result. 

The  patient  has  never  had  a  relapse,  and  has  been  in  very 
good  health  for  four  years. 

The  second  examination  of  his  intestinal  flora  showed  the 
same  germs  as  the  first. 

These  two  observations  taken  at  random  among  many 
other  similar  ones  suggest  the  following  reflections : 

While  the  supposition  was  that  one  of  the  germs  living  in 
the  large  intestine  and  contained  in  the  fecal  matter  of  our 
patients  must  be  the  cause  of  their  illnesses,  we  could  not 
assimae  a  priori  that  all  the  germs  seen  by  the  microscope  in 
fresh  or  stained  preparations  of  fecal  matter,  could  share  in 
the  cause  to  an  equal  degree.    On  the  other  hand,  as  we  had 


CASE  REPORTS  167 

no  guide  which  could  have  suggested  the  choice  of  one  germ 
rather  than  of  another,  we  chose,  to  begin  with,  the  germs 
whose  cultivation  was  easiest  and  simplest:  surface  growths 
on  gelatin  slants,  therefore,  the  commonest  aerobes. 

In  order  to  recognize  their  morphologic  characters,  their 
biochemical  and  pathogenic  properties,  each  germ  was 
isolated  in  a  pure  culture,  then  cultivated  in  different  media, 
and  lastly  injected,  either  mixed  or  separately,  into  mice. 

It  is  to  be  noted  here  at  once  that  the  mice  so  treated  never 
contracted  a  fatally  infectious  disease  in  spite  of  the  relatively 
strong  doses  (0.1  c.c.  of  a  twenty-four-hour  broth  culture) . . 
We  were  thus  handling  only  innocuous  germs. 

Another  patient  was  treated  with  a  heterogeneous  prepara- 
tion and  encouraged  by  the  result  obtained  we  entrusted  the 
same  material  to  Dr.  Labonnette  for  the  treatment  of  a 
serious  case  of  eczema. 

Observation  4.^— This  patient  had  a  long  history  of  gastro- 
intestinal disturbances  with  abdominal  and  rheumatic  pain 
at  various  times.  In  April,  1919,  a  seborrheic  eczema  of  the 
trunk  and  scalp  plus  an  oozing  eczema  of  the  perineum  and 
scrotum  appeared.  The  patient  was  given  dead  heterogeneous 
bacteria  of  which  he  took  by  mouth  2  mg.  as  an  emulsion 
daily.  Disappearance  of  the  pains  and  of  the  eczema  was 
almost  instantaneous. 

Observation  5.— Another  patient  was  treated  in  a  similar 
manner  except  that  the  development  of  pustules  indicated 
additional  treatment  with  a  staphylococcic  autovaccine 
obtained  by  culture  of  these  pustules  which  was  given. 

Observations  6  and  7.— Two  cases  of  psoriasis  were  also 
much  relieved  by  the  injection  of  entero-antigens.  In  one  of 
these,  a  second  course  of  treatment  was  begun  ten  days  after 
the  end  of  the  first  course  but  the  local  reactions  were  not 
more  severe  than  the  first— the  patient  was  therefore  not 
sensitized  by  the  first  course. 

Case  7  received  during  his  psoriasis  and  independently  the 
Pasteur  treatment  for  rabies— as  a  sequel  to  which  the  skin 
lesions  healed. 

1  Observation  3  omitted  in  English  translation. 


168     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

Two  facts  are  important:  1.  The  nearly  complete  dis- 
appearance of  the  cutaneous  lesions  in  no  case  resulted  in 
other  morbid  manifestations,  such  as  asthma  or  acute 
articular  rheumatism,  which  are  quite  frequent  when  one 
tries  to  "stifle"  the  evolution  of  cutaneous  psoriasis  by 
ointments. 

We  must  therefore  suppose  that,  in  this  case,  the  antigen 
treatment  acted  not  only  on  the  apparent  symptom,  but  on 
the  cause  of  the  lesions  as  well. 

2.  Different  antigens  are  not  equally  active.  In  one  case 
the  addition  of  an  anaerobic  bacillus,  although  in  very  small 
quantity  to  the  vaccine,  had  a  curative  action  which  was 
evidently  greater  than  that  of  all  the  other  bacteria  pre- 
viously injected. 

We  shall  see  further  on  what  may  be  the  nature  of  this 
action.  In  this  manner  25  cases  of  more  or  less  serious 
psoriasis  were  treated.  The  most  interesting  cases  were 
given  us  by  Dr.  Sabouraud  whom  I  wish  to  thank  here  for  his 
kindly  assistance. 

In  all  these  cases,  the  antigen  treatment  gave  far  better 
results  from  the  point  of  view  of  the  disappearance  of  the 
lesions,  of  its  harmlessness,  and  of  the  duration  of  cure,  than 
all  the  other  treatments  previously  advocated.  One  case 
only,  treated  for  two  months  by  an  autogenous  preparation 
taken  by  mouth  (the  patient  refusing  to  be  injected),  showed 
no  apparent  improvement. 

Struck  by  the  particular  activity  of  the  anaerobic  bacillus 
(Case  6),  we  wished  to  determine  the  importance  of  searching 
in  each  particular  case,  for  the  most  active  antigen.  Con- 
vinced of  the  harmlessness  of  our  preparations,  we  varied 
their  composition,  and  even  tried  non-bacterial  antigens. 

Thus,  of  25  cases  of  psoriasis,  12  were  treated  by  auto- 
genous bacterial  preparations,  9  by  heterogeneous  prepara- 
tions, 3  by  intravenous  injections  of  luargol.^  The  results 
obtained  in  all  cases  were  about  identical,  and  we  can  add 
that  a  psoriatic  patient,  bitten  by  a  mad  dog,  was  cured  of 
psoriasis  by  antirabies  treatment. 

1  Dr.  Dalimier  has  treated  5  cases  of  psoriasis  with  luargol.  Three  were 
completely  cured;  in  the  other  two  luargol  produced  no  results. 


CASE  REPORTS  169 

Observation  9.^— Recurrent  Psoriasis  Caused  by  Iodine.— 
One  of  these  eases  was  of  special  interest.  Treated  in  1915, 
for  the  first  time  with  an  autogenous  preparation,  for  psoriasis 
in  small  plaques  spread  all  over  the  body,  and  completely 
relieved,  the  young  woman  returned  in  1917  with  the  same 
plaques,  this  time  localized  exclusively  on  the  back  of  the 
thorax.  She  stated  that  these  plaques  appeared  some  time 
after  painting  this  region  with  tincture  of  iodine. 

Relieved  anew,  but  this  time  by  means  of  a  heterogeneous 
preparation  containing  a  mixture  of  colon  bacilli  and  of  a 
small  non-motile  bacillus,  she  returned  in  1918  covered  from 
head  to  foot  with  a  multitude  of  plaques  which  caused  intoler- 
able itching  and  which  had  appeared  after  the  ingestion  of 
an  iodized  preparation  "taken  on  the  advice  of  a  friend," 
which  was  supposed  to  cure  her  of  a  little  general  fatigue. 
This  time  a  series  of  ten  injections  of  a  mixture  prepared 
especially  with  heterogeneous  diplo-,  strepto-  and  entero- 
cocci,  conquered  the  eruption  under  the  same  conditions  as 
previously. 

The  observed  persistence  of  hypersensibility  to  iodine  in 
this  case,  makes  one  believe  that  the  treatment  by  the  differ- 
ent antigens  was  simply  symptomatic,  and  that  it  had  not 
attacked  the  fundamental  cause  of  the  evil. 

From  all  these  observations  it  seems  that,  though  the 
treatment  of  psoriasis  is  practically  very  simple,  the  theo- 
retical explanation  of  it  appears  to  be  rather  complex. 

The  identity  of  the  results  obtained  in  the  majority  of 
cases  by  autogenous  and  heterogeneous  preparations,  but  of 
very  similar  composition,  would  lead  one  to  think  that  the 
disappearance  of  psoriatic  lesions  results  from  a  reaction 
caused  by  the  same  antigens  or  by  closely  allied  antigens. 

Observation  6  indicates  the  predominating  action  of  an 
anaerobic  germ  which  we  did  not  use  in  any  other  case,  while 
Observation  7,  as  well  as  the  results  from  the  cases  treated 
with  rabbit-marrow  and  luargol,  seem  to  prove  that  the  same 
results  may  be  obtained  by  any  antigen. 

One  must,  however,  take  into  account  the  difference  in 

^  Observation  8  omitted  in  English  translation. 


170     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

doses  of  the  different  antigens  which  it  was  necessary  to  use 
to  obtain  similar  results. 

The  total  quantity  of  bacterial  bodies  used  in  from  twenty 
to  sixty  injections,  varied  from  0.4  mg.  to  2  mg.,  while  the 
total  quantity  of  marrow  injected  in  fifteen  injections  and 
of  luargol  injected  in  ten  injections  can  be  estimated  at  from 
1.5  to  2  gr.,  that  is  to  say,  a  quantity  a  thousand  times 
greater  than  that  of  the  bacteria. 

The  same  can  be  said  of  the  action  of  the  anaerobic  bacillus 
(Observation  6)  which  seems  to  be  at  least  100  times  as 
pronounced  as  that  of  all  other  bacteria  put  together. 

The  antigenic  action  on  psoriatic  lesions  could  thus  be 
explained  as  follows : 

1.  Recovery  is  determined  by  reactions  in  the  organism 
caused  by  antigens. 

2.  These  reactions  are  all  of  the  same  kind,  or  at  least 
very  similar. 

3.  The  same  results  can  be  obtained  by  different  antigens 
in  very  different  doses,  which  can  also  be  explained  by  saying 
that  antigens  are  mixtures  in  which  the  proportions  of  the 
active  substance,  always  causing  the  same  reaction,  are  very 
different. 

The  practical  suggestion  arising  from  the  above  would, 
therefore,  be  that  in  order  to  obtain  the  maximum  curative 
result  with  the  minimum  harmful  result,  one  must  search 
for  the  proper  antigen. 

B.  Asthma,.— Observation  10.— M.  M.,  aged  forty-seven  years, 
has  suffered  for  five  years  from  dyspnea  which  grows  worse 
every  year,  and  shows  itself  particularly  in  the  evening  after 
sunset,  and  lasts  all  night  until  10  a.m.  or  11  a.m.  Cold 
and  rainy  days  are  usually  much  worse  than  good  weather. 
Dyspnea  is  then  accompanied  by  coughing  with  very  difficult 
expectoration.  During  and  since  the  war,  this  condition  of 
asthma  has  become  sensibly  aggravated  on  account  of  the 
open  air  life  of  the  patient  who  had  to  dig  trenches. 

The  patient  received  in  a  total  period  of  eighteen  days 
two  series  of  eight  hypodermic  injections  of  an  autogenous 
bacterial  preparation  isolated  from  his  own  intestinal  flora 


CASE  REPORTS  171 

and  sterilized  by  heat.    This  was  a  mixture  of  colon  bacilli, 
of  Gram-positive  diplococci  and  of  Micrococcus  tetragenus. 

Several  minutes  after  the  first  injection  into  the  left  arm, 
the  patient  felt  "like  a  trembling,"  followed  by  a  tingling 
and  itching  in  the  whole  left  side  of  the  body  and  immediately 
afterward  his  respiration  became  easier.         ' 

Improvement  continued  during  the  course  of  the  treatment. 
The  patient  can  now  (eighteen  months  after)  go  out  and  work 
in  bad  weather  without  suffering  therefrom,  sleep  is  normal, 
cough  has  completely  disappeared.  The  general  state  is 
better  than  it  has  been  for  a  long  time,  the  patient  feels 
younger.  The  attacks  of  asthma  have  not  recurred  for  the 
last  eighteen  months.  Gastro-intestinal  functions,  often  dis- 
turbed previously  have  at  the  same  time  become  completely 
normal. 

Observation  11  ( Dr.  Dalimier).—  Hay  Asthma.— Mi.  J.  L., 
navy  engineer. 

Family  History.— Is/Lother  died  from  cardiac  rheumatism; 
father  died  at  seventy-nine  from  arteriosclerosis.  Neither 
parent  suffered  from  asthma.  Brother  has  slight  and  tem- 
porary hay  fever.  Both  maternal  grandparents  suffered 
from  hay  asthma. 

Personal  History.— ScsLTlatina  and  whooping-cough.  At 
twelve  years,  first  attack  of  hay  asthma.  Since  then,  every 
year  without  exception,  in  the  second  fortnight  of  May,  had 
an  attack. 

The  minutest  contact  of  a  particle  of  hay  is  sufficient  to 
bring  on  asthma.  Wheat  and  barley  have  the  same  action, 
as  also  grapevine,  but  to  a  lesser  degree.  Flowers  of  any  kind 
have  no  influence.  Honey,  however,  it  must  be  noted,  some- 
times produces  some  respiratory  and  gastro-intestinal  dis- 
turbances.   Never  any  attack  on  the  ocean. 

The  attack  is  characterized  by  a  very  pronounced  oculo- 
nasal catarrh,  coryza  and  headache;  then,  after  some  days, 
dyspnea  appears,  asthmatic  in  type,  very  troublesome, 
especially  at  night.  The  attack  lasts  two  to  three  months, 
with  alternate  increases  and  decreases,  and  leaves  behind  it 
an  early  morning  dyspnea  until  the  autumn. 

Apart  from  this  hay  fever,  this  patient  enjoys  good  health. 


172      ANTI-ANAPHYLACTIC   TREATMENT  OF  DISEASES 

During  the  last  twenty-five  years,  he  has  undergone  all 
known  treatments.  Locally  he  has  had  his  adenoids  removed, 
he  has  taken  nasal  douches  of  hot  air,  and  of  various  anti- 
septic or  analgesic  liquids.  He  has  undergone  several  thermal 
cures:  Luchon,  La  Bourboule,  Le  Mont-Dore,  where  he 
spent  several  consecutive  seasons.  He  has  tried  ozone,  which 
produced  a  notable  and  constant  increase  of  the  trouble: 
carbonic  acid,  and  pollantin,  without  any  benefit.  The  only 
measures  causing  relief  have  been  arsenic  by  mouth,  and 
"Doctor  Tucker"  applied  direct. 

Physical  examination,  April  15,  1919,  normal. 

Bacteriologic  examination  of  the  feces  shows  colon  bacilli, 
diplococci. 

Treatment.— k^  the  patient,  at  this  date  (April  15,  1919) 
showed  no  morbid  symptom,  treatment  was  given  from  a 
preventive  point  of  view.  Autogenous  entero-antigen,  8 
subcutaneous  injections,  every  fourth  day.  Very  slight  local 
reactions. 

Patient  seen  again  June  6.  Has  been  in  frequent  contact 
with  hay,  in  Paris  and  during  his  travels  in  England,  begin- 
ning about  May  15.  It  was  only  in  the  first  days  of  June 
that  oculonasal  catarrh  occurred  to  a  very  slight  degree, 
without  coryza  or  headaches.  There  is  no  trace  of  asthma. 
The  patient,  very  pleased  with  his  condition,  states  that  this 
is  the  first  time  in  twenty-five  years  that  he  has  been  so  well 
at  this  time  of  the  year,  and  he  judges  it  useless  to  undergo 
the  slightest  treatment  for  the  slight  cough  which  still 
persists. 

Observation  12  {Dr.  Dalimier).—Emphysematic  Asthma.— 
M.  F.,  aged  forty-one  years,  printing  compositor. 

Family  History.— Mother  rheumatic;  father  died  at 
seventy-eight;  no  asthma. 

Personal  History. -ArticulsLT  rheumatism  in  1900,  scarlatina 
in  1902,  appendectomy  in  1903,  bronchitis  in  1911,  slight 
chronic  lead  poisoning.  Two  nervous  crises  during  the  last 
ten  years,  corresponding  to  lead  intoxications.  No  children. 
His  wife  has  had  no  miscarriages. 

Permanent  dyspnea  since  1911,  aggravated  by  attacks  of 
asthma.    Difficulty  in  breathing  becomes  considerable  every 


CASE  REPORTS  173 

year  from  May  to  October,  and  the  patient  has  found  that  it 
is  increased  by  the  inhalation  of  dusts. 

He  has  tried  codein,  bromide,  caffein,  and  iodide,  and  the 
only  soothing  liquid  he  now  uses  is  "Doctor  Tucker's  Asthma 
Cure." 

Classed  as  unfit  for  active  service  on  account  of  asthma 
and  emphysema. 

Examination.— An  obese  man,  heavy  eater,  evident  signs 
of  very  pronounced  pulmonary  emphysema.  Heart  normal, 
blood-pressure  160/90.  Urine:  Neither  sugar  nor  albumin. 
Slight  pupillary  inequality.  Dyspnea  on  exertion  with 
inspiratory  spasm. 

Diagnosis.— Chronic  pulmonary  emphysema,  with  inter- 
current crises  of  asthma. 

Fecal  Examination.— BsicteTi8i\  flora:  Colon  bacilli,  diplo- 
cocci,  enterococci. 

Treatment.— Autogenous  entero-antigen.  Ten  subcuta- 
neous injections,  one  every  fourth  day.  Violent  reaction  at 
each  injection  consisting  of  local  pain  with  inflammatory 
halo  the  next  day,  definite,  even  painful  exaggeration  of  the 
respiration  for  twenty-four  hours.  After  the  end  of  this 
reaction,  the  patient  feels  each  time  much  improved.  After 
the  termination  of  the  series  of  injections,  he  has  no  more 
dyspnea ;  he  gives  as  illustration  of  his  improvement  the  fact 
that  "he  can  now  climb  the  Sorbonne  hill  by  the  rue  St. 
Jacques  without  effort  or  trouble,"  whereas  during  the  last 
ten  years  he  was  unable  to  do  so. 

C.  Other  Cases.— Detailed  case  reports  of  32  additional 
cases  comprising  a  wide  variety  of  chronic  morbid  states 
have  been  omitted  in  this  English  translation. 

The  reports  picture  the  remarkable  results  following  the 
use  of  dead  bacteria  in  the  form  of  an  emulsion  (a  vaccine) 
and  administered  either  by  mouth  or  by  subcutaneous  injec- 
tion. In  most  cases,  improvement  is  immediate.  Practically 
complete  relief  of  sxinptoms  is  experienced  by  the  majority 
of  the  patients  after  at  most  fifteen  treatments  at  one-  to 
three-day  intervals. 

These  cases  include  those  with  such  diagnoses  as  the 
following:    Neurasthenia,  scleroderma,  dysmenorrhea,  meno- 


174     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

pause,  a  large  number  of  gastro-intestinal  disturbances 
including  several  forms  of  enteritis  and  chronic  diarrhea, 
gastroptosis,  neuro-arthritis,  rheumatism  and  the  gastro- 
intestinal symptoms  of  tuberculosis. 

SUMMARY  OF  OBSERVATIONS. 

Two  hundred  and  sixty  cases  of  chronic  disease,  similar  to 
those  quoted  were  treated  in  this  manner  (with  the  collabora- 
tion of  Drs.  Cazin,  Dalimier,  Delettre,  Dominici,  Labonnette, 
Raspali,  Richard,  Smiechowska,  and  others). 

In  analyzing  these  cases,  one  finds  from  the  first  that  the 
treatment  by  antigens  prepared  from  the  germs  of  intestinal 
flora,  showed  itself  efficient,  not  only  in  cases  of  digestive 
disturbance  and  in  urticaria,  but  also  in  many  other  cases, 
which  appear  to  have  no  direct  relation  with  the  functions  of 
the  digestive  apparatus.  We  must,  therefore,  conclude  that, 
even  if  the  primary  causes  of  these  diseases  differ,  the  reactions 
determining  the  pathologic  symptoms  must  always  be  of  the 
same  nature. 

On  the  other  hand,  the  minuteness  of  the  curative  doses 
(2  to  3  mg.  by  mouth  and  a  few  hundredths  of  a  milligram  in 
hypodermic  injections)  and  the  rapidity  of  the  reactions 
caused  by  these  doses,  suggest  that  the  bacterial  antigens 
contain  a  much  greater  proportion  of  the  active  substance 
than  peptone,  animal  proteins,  milk  or  any  serum  which  in 
certain  cases  of  urticaria,  asthma  (Widal,  Nolf,  Paignez  and 
Vallery-Radot  Pasteur,  and  others),  give  similar  curative 
results  in  doses  a  hundred  or  a  thousand  times  greater. 

The  action  of  the  bacterial  preparations  which  were  used 
in  the  cases  quoted  above  were  probably  not  "specific," 
in  the  sense  of  the  antigens  used  in  the  vaccinotherapy  of 
Wright,  but  their  actions  are  remarkably  selective. 

GENERAL  AND  LOCAL  REACTIONS  CAUSED  IN  THE 
ORGANISM  BY  ENTERO- ANTIGENS. 

Action  on  the  Intestinal  Flora.— We  have  already  seen  that 
the  injections  or  the  ingestion  of  our  preparations,  at  the 


REACTIONS  CAUSED  IN  THE  ORGANISM         175 

doses  used,  do  not  appreciably  modify  the  intestinal  flora  of 
the  patients.  A  decrease  of  one  bacterial  species  or  another 
is  sometimes  observed  in  the  stools  after  a  fortnight's  or  a 
month's  treatment;  but  the  same  changes  are  observed  in 
normal  non-treated  persons;  so  that  these  passing  decreases 
cannot  be  attributed  to  the  action  of  the  treatment. 

We  have  never  found  a  complete  disappearance  of  any 
bacterial  species  living  normally  in  fecal  matter;  on  the  other 
hand,  we  have  found  that  certain  pathogenic  bacteria  such 
as  the  paratyphoids  or  certain  strains  of  colon  bacilli  com- 
pletely disappeared  after  treatment  by  injection  or  ingestion 
of  such  dead  bacteria. 

We  have  never  observed  any  marked  agglutination  reaction 
with  any  species  of  injected  bacteria  in  the  serum  of  treated 
patients  fifteen,  thirty  or  sixty  days  after  the  end  of  the 
treatment.  The  conclusion  is  therefore  that  the  treatment, 
as  applied,  did  not  cause  the  formation  of  ''antibodies  in 
excess"  in  appreciable  quantity. 

General  Reactions.— The  first  striking  phenomenon  after 
the  first,  or  the  first  few  injections  or  ingestions  of  an  auto- 
genous or  heterogeneous  preparation,  is  the  rapid  change  of 
the  patient's  general  condition.  A  direct  action  on  the  ner- 
vous system  is  nearly  always  observed  which  is  shown  by 
lassitude,  a  need  for  sleep,  relaxation  and  rest,  a  general  lull 
which  is  in  no  wise  disagreeable,  which  may  last  several  hours, 
rarely  two  or  three  days,  and  is  usually  followed  by  a  long 
period  (several  weeks  or  months)  of  surprising  exhilaration. 
The  patient  feels  himself  "being  born  again,"  he  feels  a  sur- 
prising need  for  physical  and  mental  activity,  and  can  under- 
take without  fatigue  work,  which  a  few  days  before  would 
have  seemed  beyond  his  strength.  Sometimes  the  period  of 
lassitude  is  so  short  and  slight,  that  the  period  of  exhilaration 
seems  to  appear  all  at  once.  In  other,  less  frequent  cases, 
the  first  doses  of  the  preparation  are  followed  by  headaches 
which  may  last  for  several  hours,  by  chills  or  by  a  slight  rise 
in  temperature.  Still  more  rarely,  the  symptoms  of  the  dis- 
ease are  seen  to  increase  slightly.  Asthmatics  may  have  a 
more  violent  crisis,  the  itching  in  dermatoses  increases, 
psoriasis  plaques  become  darker;  but  these  aggravations 


176     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

never  last  long,  are  not  a  contra-indication  to  further  treat- 
ment, and  are  always  followed  by  appreciable  and  rapid 
improvement.  At  the  most,  it  may  sometimes  be  necessary 
to  diminish  the  dose.  If  this  is  necessary  only  one-tenth  or 
even  one-hundredth  is  given. 

Local  Reactions.— When  the  treatment  is  applied  in  the 
form  of  injections,  the  reactions  at  the  point  of  inoculation 
vary  considerably.  Sometimes  redness,  and  a  more  or  less 
painful  zone  may  persist  for  one  to  three  days:  at  other 
times  the  injection  leaves  no  other  trace  than  the  small 
needle  point. 

If  the  treatment  is  by  ingestion,  one  often  notes,  on  the 
first  and  second  days  a  slight  pain  in  the  epigastrium.  This 
pain  is  only  slight  and  manifests  itself  only  on  pressure  in 
the  epigastrium. 

Whether  the  treatment  is  applied  by  injection  or  by  inges- 
tion, palpation  discloses  a  sensitiveness  over  the  gall-bladder 
and  over  the  posterior  part  of  the  liver  between  the  eleventh 
and  twelfth  ribs,  near  the  upper  edge  of  the  right  kidney. 

The  kidney  is  never  tender,  but  undergoes  important 
functional  modifications.  A  phenomenon  is  observed  similar 
to  that  which  often  characterizes  the  terminal  period  of  acute 
infections  (typhoid  fever,  influenza),  namely,  polyuria. 

The  reaction  on  the  gastro-intestinal  functions  is  quite 
remarkable.  No  matter  what  the  preparation,  autogenous 
or  heterogeneous,  or  whether  administered  by  injection  or 
by  ingestion,  it  acts  as  a  regulator  of  the  digestion  and  of 
evacuations. 

In  those  cases  where  gastro-intestinal  functions  are  normal, 
for  instance  in  psoriasis,  the  beginning  of  the  treatment  is 
characterized  by  a  tendency  toward  constipation,  which 
may  last  several  days  and  recovers  spontaneously  without 
medication. 

The  circulation  is  also  influenced  by  the  action  of  the 
entero-antigens.  In  the  cases  of  either  increased  or  decreased 
blood-pressure,  one  often  sees  hypertension  diminish  by  10, 
20  or  30  mm.  and  hypotension  increase  by  10  or  20  mm. 
after  the  treatment. 


THEORY  OF  CURATIVE  REACTIONS  177 

THEORY  OF  CURATIVE  REACTIONS.     KENDALL'S 
EXPERIMENT. 

How  then  may  we  explain  the  nature  as  well  as  the 
mechanism  of  these  curative  reactions? 

In  order  to  answer  these  questions  we  must  remember 
that: 

1.  Every  normal  or  abnormal  function  of  an  organ,  a 
gland  or  a  tissue  depends  on  the  central  nervous  system,  so 
that  all  the  modifications  of  the  physiological  equilibrium  of 
a  cell  may  be  caused  or  arrested  by  the  direct  or  reflex  action 
of  the  nervous  centers. 

2.  Whatever  be  the  cause  of  a  lesion  or  of  a  functional 
disturbance  of  an  organism,  the  pathologic  symptom  will 
be  always  caused  by  a  nervous  reaction. 

3.  Each  functional  disturbance  of  a  cell  can  be  but  the 
rupture  of  the  nutritive  and  respiratory  equilibrium  of  this 
cell. 

In  this  way,  an  emotion  causes  in  certain  people  enteritis, 
dermatosis  or  an  attack  of  asthma.  This  means  that  certain 
psychic  centers  have  reacted  on  the  trophic  centers  of  the 
bulb,  that  their  excitation  has  interfered  with  the  capillary 
circulation  of  the  intestinal  or  pulmonary  mucosa  or  of  the 
skin. 

It  is  therefore  in  the  excitation  of  the  nervous  centers 
that  the  initial  cause  of  the  disease  must  be  looked  for;  it  is 
likewise  the  nervous  centers  which  prepare  the  lesions  and 
which  set  off  pathologic  symptoms  through  the  reflex  action 
of  the  lesions. 

In  many  other  more  numerous  cases,  the  initial  cause  of 
the  disease  is  an  agent  which  is  exterior  to  the  organism:  a 
poison,  an  antigen  or  a  traumatism.  It  is  this  agent  which 
disturbs  the  nutritive  equilibrium  of  the  cells  and  which 
thus  prepares  the  lesions;  but  the  maintenance  of  these 
lesions  and  the  reactions  causative  of  pathologic  symptoms 
are  still  governed  by  the  nerve  centers. 

To  make  this  argument  more  plain  let  us  suppose  the  pres- 
ence of  a  stone  in  the  gall-duct.  The  stone  manifests  itself 
by  violent  pains,  because  the  walls  of  the  canal  contract 
12 


178     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

before  and  behind  the  stone  and  prevent  it  from  passing. 
Morphine  or  atropine  will  relieve  these  pains  by  relaxing  the 
walls  of  the  canal  so  that  the  stone  continues  on  its  way 
without  causing  the  slightest  harm.  The  primary  cause  of 
the  evil  here  is  therefore  the  formation  of  the  stone  and  its 
entry  into  the  canal.  It  is  likewise  the  stone  which  prepares 
the  traumatic  lesion  of  the  walls  of  the  canal,  but  it  is  the 
reflex  reaction  of  the  nerve  centers  which  maintains  the  lesion 
and  the  pain.  To  abolish  the  sensitiveness  of  the  nerve 
centers  is  to  end  the  contractions  and  the  pain. 

In  the  same  order  of  ideas,  an  anaphylactic  state  is  created 
by  preparatory  injections  of  an  antigen,  and  a  fatal  crisis 
is  precipitated  by  the  second  injection  of  the  same  antigen, 
but  this  crisis  can  be  avoided  by  the  absorption  of  a  suffi- 
cient dose  of  alcohol  or  ether  (Roux  and  Besredka),  or  also 
by  an  injection  of  adrenalin  (Milian).  Here  the  primary, 
initial  cause  of  the  pathologic  state  is  .the  preparatory  injec- 
tion of  the  antigen  which  causes  the  formation  of  the  anti- 
body by  certain  cells.  The  resulting  lesion  is  localized  in 
these  cells;  there  is  no  symptom.  The  anaphylactic  crisis 
is  caused  by  the  action  on  the  nerve  centers  of  the  precipi- 
tate which  results  from  the  combination  in  the  blood  of  the 
excess  antibody  with  the  antigen  of  the  second  injection, 
suddenly  disturbing  the  general  nutritive  equilibrium  and 
more  especially  that  of  the  nerve  centers.  A  sufficient  dose 
of  alcohol  or  ether  anesthetizes  the  nerve  centers,  while 
adrenalin  contracts  the  capillaries  and  prevents  the  precipi- 
tate from  reacting  in  them. 

As  in  the  case  of  stone,  so  in  the  case  of  the  antigen,  it  is 
through  the  nerve  centers  that  the  pathologic  manifestations 
may  be  relieved  or  prevented. 

It  is  interesting  to  quote  here,  on  this  subject,  an  accurate 
experiment  of  E.  C.  Kendall,  inspired  by  the  work  of  Crile 
on  the  role  of  the  suprarenal  capsules  in  Barlow's  disease. 
This  experiment  as  reviewed  in  the  Presse  Medicate^  deserves 
to  be  quoted  in  toto: 

"Operating  on  dogs,  Kendall  slowly  injected  intravenously 

1  Kendall,  Edward  C:  Experimental  Hyperthyroidism,  Jour.  Am.  Med. 
Assn.,  lix,  612.     From  the  Presse  Midicale,  1917,  No.  59,  p.  612. 


I 

I 


THEORY  OF  CURATIVE  REACTIONS  179 

amino-acids.  The  animals  had  been  previously  thyro- 
parathyroidectomized,  and  into  some  of  them  there  was 
injected,  before  or  during  the  introduction  of  amino-acids, 
the  active  principle  of  the  thyroid  (Kendall). 

"The  observed  results  allow  of  the  classification  of  the 
animals  into  two  groups:  Some  had  abundant  diuresis  and 
their  temperature  increased,  sometimes  reaching  113°. 
Their  respiration  became  accelerated,  and  deep;  their  pulse 
became  rapid.  Nervous  excitability  was  increased,  and  there 
were  rigors  accompanied  by  spasms  which  suggested  the 
contractions  of  tetany. 

"Other  animals  showed  quite  different  manifestations: 
urine  was  scarce,  temperature  remained  normal,  pulse  was 
small  and  regular,  respiration  feeble  and  superficial,  nervous 
system  greatly  depressed. 

"Between  these  two  types  intermediate  forms  could  be 
observed,  and  sometimes  tetanus  was  seen  to  develop  after 
a  period  of  depression. 

"Among  the  conditions  intervening  to  modify  these 
symptom-complexes,  the  influence  of  food  is  important. 
The  depressive  form  is  observed  with  digesting  animals, 
the  tetanic  form  with  those  fasting  for  twenty-four  or  forty- 
eight  hours. 

"The  effects  of  thyroid  extract  are  quite  varied.  If 
thyroid  extract  is  introduced  before  the  injection  of  the 
amino-acids,  the  depressive  phenomena  predominate. 

"Since  amino-acids  determine  under  experimental  condi- 
tions, results  diametrically  opposed,  one  is  led  to  suppose 
that  they  undergo  in  the  organism  changes  which  modify 
their  properties.  It  has  long  been  known  that  they  are 
transformed,  at  least  in  part,  into  ammonia  and  urea.  It  was 
therefore  interesting  to  determine  the  proportions  of  these 
substances  in  the  urine  excreted  by  these  experimental 
animals. 

"When  the  symptoms  of  nervous  excitation  predominate 
the  quantity  of  urine  is  often  considerably  increased.  A  dog 
weighing  twenty-four  pounds,  in  one  hour  excreted  1760 
c.c.  of  urine.  Before  the  experiment,  urea  formed  80  per 
cent,  of  the  total  nitrogen  in  the  urine  but  during  the  experi- 


180     ANTI-ANAPHYLACTIC  TREATMENT  OF  DISEASES 

merit,  urea  fell  to  15  per  cent.  As  the  ammonia  did  not 
increase,  the  conclusion  is  that  the  urine  contains  a  new 
substance.  This  new  substance  (X)  deserves  the  name  of 
preurea,  because  if  the  urine  stands  for  twentj-four  hours, 
the  quantity  of  urea  increases  up  to  a  double  amount. 

"In  making  the  same  analyses  of  the  urine  of  these  dogs 
affected  with  depressive  manifestations,  an  increase  of 
ammonia  is  observed,  but  no  substance  X  is  found.  The 
conclusion  was  therefore  arrived  at,  that  if  the  ammonia 
from  the  amino-acids  is  transformed  rapidly  into  X, 
phenomena  of  excitation  appear;  if  it  is  transformed  only 
slowly,  depressive  manifestations  predominate. 

"The  substance  X,  which  might  be  the  cause  of  tetany, 
is  normally  transformed  into  urea  by  the  parathyroid  glands, 
and  this  fact  explains  perfectly  the  role  of  these  glands  in 
the  development  of  nervous  manifestations.  But  in  which 
organ  is  the  ammonia  transformed  into  X  (preurea)? 
Kendall  supposes  that  it  is  in  the  suprarenals,  because  the 
removal  of  these  glands  results  in  depressive  phenomena. 

"To  verify  this  hypothesis,  he  made  the  following  experi- 
ment: He  removed  the  cortical  layer  of  the  suprarenal  of 
an  etherized  cat,  and  submitted  it  to  digestion  with  ammo- 
nium carbonate.  This  salt  was  transformed  into  a  special 
substance  different  from  urea.  In  repeating  the  experiment 
with  suprarenals  taken  from  cattle  or  from  other  cats,  the 
result  was  absolutely  negative;  the  ammonium  carbonate 
remained  intact. 

"For  a  time  Kendall  was  unable  to  understand  the  cause 
of  these  contradictions.  Suddenly  he  remembered  that 
before  being  etherized,  the  first  cat  had  been  for  some  time 
in  the  presence  of  two  dogs  which  had  terrorized  it.  This 
was  a  flash  of  light.  The  ferment  which  transforms  the 
ammonia  into  preurea  must  be  produced  by  the  influence  of 
nervous  excitation.  He  resumed  his  experiments  on  cats 
previously  frightened,  and  found  again  in  the  cortex  of  the 
suprarenal  the  ferment  he  was  looking  for.  He  also  obtained 
a  positive  result,  not  however  constantly,  by  submitting  the 
suprarenals  to  the  action  of  an  electric  current. 

"Besides  nervous  influences,  one  must  always  consider 


INFLUENCE  OF  THE  NERVOUS  SYSTEM        181 

the  action  of  hormones  in  the  blood.  As  the  suprarenal 
cortex  acts  on  ammonium  carbonate  and  changes  it  to  pre- 
urea,  it  is  probable  that  this  salt  stimulates  the  functions 
of  the  gland,  at  least  under  certain  conditions.  It  was 
therefore  of  interest  to  resume  the  study  of  the  effects  pro- 
duced by  intravenous  injections  of  the  ammonium  salt. 

''As  with  amino-acids,  both  depression  and  excitation 
are  observed.  In  the  first  case  the  animal  was  feeble  and  its 
respiration  remained  light  and  superficial;  in  the  second,  the 
animal  was  strong,  and  its  respiration  became  deep.  A 
process  of  oxidation  must  therefore  take  place  to  activate 
the  suprarenal  cortex. 

"These  two  reaction-types  are  accompanied  by  abso- 
lutely characteristic  urinary  modifications.  When  the 
depression  phenomena  predominate,  the  urine  contains 
ammonia;  when  the  tetanus  manifestations  predominate, 
the  ammonia  decreases.  Thus  by  analyzing  the  urine,  all  the 
unseen  phases  of  the  experiment  are  followed. 

"These  facts  all  demonstrate  the  role  of  the  suprarenal 
in  the  development  of  the  nervous  excitations  attributed  to 
the  thyroid,  and,  it  must  be  added,  also  demonstrate,  the 
role  of  the  nervous  excitation  on  the  functioning  of  the 
suprarenals. 

"The  main  thing  to  remember  is  that  this  experiment  brings 
out  with  accuracy  the  nature  of  the  functional  and  chemical 
reactions  caused  by  emotion.  It  was  fright  that  caused  the 
formation  in  the  cortical  layer  of  the  cat's  suprarenals  of 
the  substance  X,  the  preurea  which  is  not  normally  formed 
there,  but  which  also  appears  after  the  injections  of  large 
doses  of  amino-acids  into  the  veins  of  parathyroidectomized 
animals.  Here  the  injection  of  amino-acids  causes  a  big 
nervous  excitation  which  determines  in  the  cortex  the  same 
reaction  as  emotion:  the  formation  of  preiirea.^' 

THE  INFLUENCE  OF  THE  NERVOUS  SYSTEM. 

We  have  seen  above  how  all  kinds  of  morbid  states  may 
be  cured  by  injections  or  ingestions  of  antigens,  and  we 
have  pointed  out  that  it  is  difficult,  in  these  cases,  to  admit 


182     ANTI-ANAPHYLACTIC   TREATMENT  OF  DISEASES 

a  direct  action  of  the  medicine  on  the  intestinal  germs  or  on 
the  lesions.  We  have  definitely  shown  that,  in  general,  the 
pathologic  manifestations  of  a  lesion  can  be  caused  only  by 
nervous  reactions,  and  we  have  also  seen  that,  in  preventing 
the  nerve  centers  from  acting,  it  is  possible  to  prevent  or  to 
cure  a  hepatic  or  nephritic  colic;  we  could  therefore  deduce 
that  our  bacterial  preparations  were  curative  only  on  account 
of  their  action  on  the  nerve  centers. 

A  confirmation  of  this  hypothesis  can  be  found  in  the 
results  sometimes  obtained  by  a  method  applied  in  China 
from  time  immemorial,  chilled  "cha-chin,"  from  w^hich 
"  reflexotherapy "  is  derived,  as  practised  during  these  last 
years  by  several  European  doctors,  and  propagated  in  France 
particularly  by.  Peter  Bonnier. 

We  have  not  been  able  to  obtain  definite  information 
about  "cha-chin."  According  to  several  European  doctors, 
who  have  sojourned  in  China,  the  "cha-chin"  method  con- 
sists in  pricking  the  patients  with  long  needles  at  different 
parts  of  the  body,  and  particularly  at  the  joints,  which  must 
be  pierced,  right  through.  Chinese  doctors  obtain  by  this 
method,  and  apparently  often,  rapid  cures,  even  in  serious 
cases  of  acute  infectious  diseases,  and  more  particularly  in 
cholera. 

Peter  Bonnier  treated  all  kinds  of  infirmity  and  chronic 
disease  (deafness,  nervous  ticks,  asthma,  certain  dermatoses, 
gastro-intestinal  disturbances)  by  touching  certain  points 
of  the  nasal  mucosa  with  a  galvano-cautery.  According  to 
his  idea,  by  cauterizing  the  termination  of  the  trigeminal 
nerve,  he  caused  a  reaction  in  the  bulbar  centers,  which  then 
acted  to  restore  the  peripheral  cellular  functions. 

Whatever  the  explanation,  there  are  cases  of  asthma  and 
of  serous  mucomembranous  enteritis  which  have  resisted  all 
other  known  treatments  and  have  been  undoubtedly  and 
radically  cured  by  Bonnier.  In  several  of  these  cases  the 
cure  has  lasted  for  over  ten  years. 

Is  it  possible  to  attribute  today  the  curative  results  of 
reflexotherapy— it  appears  that  this  method  has  proved 
itself  of  certain  efficacy  only  in  the  ratio  of  1  case  in  10— to 
reactions  of  a  kind  differing  from  nervous  shock? 


INFLUENCE  OF  THE  NERVOUS  SYSTEM        183 

When  we  consider  the  infinitely  small  quantities  of  our 
bacterial  antigens  which  proved  active  in  our  trials  (200  to 
300  mg.,  and  even  less  in  Observation  6),  we  might  assume 
that  the  tissues  destroyed  by  cauterization  or  by  injections, 
and  later  resorbed,  act  as  antigens;  but  even  then  we  would 
still  have  to  explain  the  nature  of  the  reactions  caused  by 
these  antigens.  The  problem  would  be  shifted,  but  not 
solved. 

We  have  seen  above,  in  the  section  on  anesthesia,  in  the 
experiment  of  Roux  and  Besredka,  in  Kendall's  experiment, 
how  predominating  the  role  of  the  nerve  centers  is  in  all 
preventive,  curative  or  pathologic  reactions. 

In  these  cases,  the  action  of  the  nerve  centers  on  the 
symptoms,  and  sometimes  on  the  deeper  causes  of  lesions  is 
indisputable,  and  as  it  must  be  admitted  in  comparing  the 
results  obtained  by  bacterio-  and  reflexotherapy,  that  in 
both  methods  the  nature  as  well  as  the  mechanism  of  the 
curative  reactions  must  be  the  same. 

The  injections  of  antigens,  as  well  as  the  cauterization  of 
the  terminations  of  the  trigeminal,  cause  local  curative 
reactions  by  the  excitation  and  the  reflex  action  of  certain 
nerve  centers. 

In  the  cases  treated  in  our  laboratory  and  by  our  colla- 
borators, nearly  identical  results  have  been  obtained  by 
autogenous  or  heterogeneous  preparations. 

Diseases  apparently  as  different  as  psoriasis,  eczema, 
enteritis,  asthma,  jaundice  or  chronic  appendicitis  have 
been  treated  with  equal  success  by  the  same  heterogeneous 
preparation. 

From  the  point  of  view  of  the  theories  of  immunity  and 
anaphylaxis,  as  well  as  from  that  of  the  therapeutic  indica- 
tion which  may  result,  it  is  therefore  very  important  to  note 
that  in  the  diseases  considered  (and  probably  in  many  others) : 
the  curative  reactions  are  not  determined  by  the  chemical 
affinities  which  may  exist  between  the  curative  substance, 
the  pathogenic  agent  and  the  diseased  tissue  or  the  antibody 
produced,  but  by  an  elective  action  of  the  curative  product 
on  the  nerve  centers. 

If  the  anatomy  and  the  physiology  of  the  nerve  cells  were 


184     ANTI^ANAPHYLACTIC  TREATMENT  OF  DISEASES 

known  down  to  their  intimate  details,  if  we  knew  which 
nerve  termination  had  to  be  pricked,  burned  or  excited  in 
order  to  affect  a  given  nerve  center  and  produce  the  desired 
general  or  local  reaction,  it  is  certain  that  on  this  knowledge 
one  might  base  a  method  of  treatment  as  efficient  as  it  would 
be  easy  to  apply;  but  as  long  as  our  ideas  on  this  subject  are 
as  inexact  as  they  are  today,  the  results  of  this  treatment 
will  depend  much  more  on  chance  than  on  the  knowledge  of 
the  operator. 

We  are  much  better  equipped  today  to  fight  chronic  dis- 
ease efficiently  and  intelligently  by  antigens. 

The  bacteriotherapy  and  the  choice  of  the  most  efficient 
curative  antigen  in  each  particular  case  are  not  dictated  by  a 
chance  discovery.  This  method  is  the  result  of  logical  deduc- 
tions based  on  a  long  series  of  experimental  researches,  and 
confirmed  by  other  experiments  which  allow  us  all  to  appre- 
ciate its  value. 


cha;pter  XII. 

GENERAL  SUMMARY:  THEORETICAL 
DEDUCTIONS. 

1.  The  work  of  Pasteur,  of  his  pupils,  and  successors  on 
pure  cultures  and  on  the  specificity  of  germs  in  infectious 
diseases  have  led  to  the  practice  of  specific  preventive  vaccina- 
tion with  bacterial  cultures  of  attenuated  virulence  or  with 
sterilized  bacterial  bodies. 

2.  The  work  of  Roux  and  Yersin  and  of  Behring  and 
Kitasato  (1889-93)  on  bacterial  toxins  and  antitoxic  sera 
has  resulted  in  the  practice  of  specific  serum  therapy  in  ill- 
nesses caused  by  toxins  (diphtheria,  tetanus,  certain  kinds 
of  pneumonias,  of  dysenteries,  etc.). 

3.  The  work  of  Hayem  (1885-1890),  Kraus  (1897), 
Belfanti  and  Carbone  (1898),  J.  Bordet  (1898),  Ehrlich 
(1899),  and  others,  on  the  reactions  caused  in  the  animal 
organism  by  repeated  injections  of  blood  serum,  bacterial  cul- 
tures and  of  other  heterogeneous  albuminoid  liquids,  have 
resulted  in: 

(a)  The  conception  and  application  in  medical  practice 
of  Wright's  specific  vaccinotherapy  in  the  treatment  of  acute 
infectious  diseases. 

(6)  The  discovery  of  Charles  Richet's  anaphylaxis  (1902) 
and  the  practical  application  of  the  specific  anaphylaxis  of 
Besredka  and  Steinhardt  (1907). 

4.  At  the  same  time  the  researches  of  Schmidt  Mulheim 
(1880)  on  peptones  of  Roger  and  Josue,  Delezenne  and  Beso 
(1893-1895),  Gley  and  Le  Bas,  Ancel  and  Bouin  (1897-1907), 
and  others  on  organ  extracts  have  led  to  non-specific  tachy- 
phylaxis; the  researches  of  Widal  and  his  collaborators, 
Abrami,  Brissaud,  Lermoyez,  and  others,  on  paroxysmal 
hemoglobinuria;   of  Nolf,   James  W.  Jobling,  Pagnez  and 


186  THEORETICAL  DEDUCTIONS 

Vallery-Radot-Pasteur,  and  others  (1910-1917),  on  the 
curative  properties  of  peptones,  autogenous  sera  or  heter- 
ogeneous sera,  of  heterogeneous  bacterial  antigens  in  the 
treatment  of  acute,  chronic  or  infectious  diseases,  have 
resulted  in  non-specific  sero-  or  proteosotherapy. 

5.  Our  researches  (1912-1919)  on  the  properties  and  the 
action  of  the  organism  of  the  colloidal  substances  obtained 
by  synthesis,  and  particularly  of  arsenobenzenes  proved  to 
us  that  all  the  phenomena  of  immunity  anaphylaxis  and 
of  tachyphylaxis,  and  the  methods  of  preventive  vaccina- 
tion of  vaccinotherapy,  of  anti-anaphylaxis,  of  serobacterio- 
therapy  and  of  proteosotherapy,  specific  or  non-specific 
derived  from  such  phenomena  are  caused  by  reactions 
which,  in  principle,  are  of  the  same  kind. 

6.  Our  researches  in  the  etiology  and  nature  of  chronic 
diseases,  inspired  by  the  whole  of  the  preceding  work,  have 
resulted  in  the  application  in  practice  of  non-specific  but 
selective  bacteriotherapy. 

The  application  of  this  last  method  is  based  on  the  follow- 
ing considerations : 

1.  Any  congestion  of  the  gastro-intestinal  mucous  mem- 
brane may  be  the  cause  of  the  passage  into  the  blood  of 
incompletely  digested  albumins  (bacterial  or  alimentary) 
which  act  as  antigens. 

2.  Every  antigen,  heterogeneous  to  the  organism,  will 
cause  in  this  organism  a  state  of  immunity  and  of  anaphy- 
laxis; it  will  be  therefore  more  or  Jess  harmful. 

3.  Every  specific  curative  or  preventive  antigen  (vaccino- 
therapy, anti-anaphylaxis)  will  prevent  or  cure  disease,  but 
will  at  the  same  time  reinforce  the  specific  condition  of 
immunity-anaphy  laxis . 

4.  If  a  certain  number  of  different  antigens  can  give,  in  a 
given  disease,  the  same  preventive  or  curative  result;  if,  for 
example,  typhoid  fever  can  be  treated  with  equal  success 
by  specific  bacteriotherapy  or  by  peptone  (Nolf),  an  attack 
of  asthma  or  urticaria  by  the  injection  of  a  serum,  by  an 
autogenous  or  heterogeneous  bacterial  preparation  or  by 
peptone;  syphilis  or  trypanosomiasis  by  atoxyl,  arseno- 
benzene  or  luargol;  these  results  will  be  obtained  by  very 


r 


THEORETICAL  DEDUCTIONS  187 

different  doses.  Where  several  grams  of  serum  or  of  peptone 
will  be  needed,  a  few  hundredths  of  a  milligram  of  bacterial 
bodies  will  suffice;  several  grams  of  atoxyl  or  of  arseno- 
phenylglycin  will  produce  the  same  effect  as  a  few  decigrams 
of  luargol. 

In  order  to  cause  a  minimum  of  harmful  result  and  at 
the  same  time  a  maximum  of  curative  result,  we  must  there- 
fore look  for  the  most  selective  products  for  each  particular 
case,  or  rather  groups  of  antigens  for  those  groups  of  diseases 
which  present  a  group  of  characteristics  in  common. 

It  would  thus  be  very  important  to  prefer  heterogeneous 
curative  antigens  to  specific  antigens  whenever  possible  on 
condition  that  they  be  very  selective,  because  in  this  way  we 
will  avoid  the  reinforcement  of  the  existing  state  of  immunity- 
anaphylaxis,  and  the  small  doses  of  heterogeneous  antigen 
will  not  cause  the  formation  of  a  new  immunity-anaphylaxis. 

THEORETICAL  DEDUCTIONS. 

1.  Disease,  no  matter  what  its  nature  and  its  manifesta- 
tions is  always  the  result  of  the  breaking-down  of  the  normal 
nutritive  equilibrium  of  certain  cells.  This  breakdown  of 
equilibrium,  resulting  in  characteristic  lesions  and  symptoms 
for  each  disease  may  have  as  origin: 

(a)  Either  crystalloid  chemical  poisons  which  fix  them- 
selves directly  on  the  cellular  matter  and  modify  its  com- 
position and  its  reactions. 

(6)  Or  antigens  which  bring  about  the  passage  into  the 
blood  of  antibodies  in  excess  and  oblige  certain  cells  to  per- 
form greater  work  to  the  detriment  of  their  normal  functions; 

(c)  A  direct  excitation  of  certain  nerve  centers  by  a  poison, 
an  antigen  or  an  emotion. 

Pathologic  manifestations  will  always  result  from  the  reflex 
reactions  of  the  nerve  centers. 

2.  Most,  if  not  all,  non-contagious  chronic  diseases,  as 
well  as  idiosyncrasies,  have  as  primary  cause  antigens  of 
intestinal  origin;  as  determining  cause,  the  anaphylactic 
state  of  certain  tissues;  as  "exciting"  causes,  the  reflexes  of 
the  nerve  centers. 


18$  THEORETICAL  DEDUCTIONS 

3.  All  and  any  medicines  or  methods  of  local  or  general 
application  which  have  shown  themselves  to  be  in  any  degree 
efficacious  in  the  treatment  of  these  diseases,  act  fundamen- 
tally through  the  nerve  centers.  The  degree  of  their  efficacy 
depends  on  their  greater  or  less  selective  action  on  a  given 
nerve  center,  or  portion  of  nerve  center. 

THE  THEORIES  OF  IMMUNITY,  OF  ANAPHYLAXIS  AND 
OF  ANTI- ANAPHYLAXIS. 

In  order  to  understand  the  cause  and  the  nature  of  the 
reactions  which  an  organism  may  or  must  undergo  under 
the  influence  of  external  agents,  as  well  as  the  possible  effect 
of  these  reactions  on  its  evolution,  it  is  necessary  to  consider 
the  following: 

1.  The  essential  physicochemical  properties  of  living 
matter. 

2.  The  structure  of  a  living  being. 

3.  The  general  rules  determining  the  nutrition  of  the 
organism  and  of  its  component  cells,  or,  in  other  words, 
the  conditions  under  which  an  organism  can  assimilate  the 
substances  which  it  needs  in  order  to  keep  its  tissues  living 
and  multiplying  and  to  furnish  energy  to  perform  its  work. 

Without  going  into  too  great  detail  our  knowledge  today 
may  be  summarized  as  follows: 

Living  matter  as  found  in  the  cells  of  all  living  beings,  is 
made  of  albuminoid  substances  of  which  the  composition 
and  the  physicochemical  properties  are  very  uniform. 

Albumins  are  combinations  of  four  elements  (C,  H,  O,  N) 
in  fairly  constant  proportions,  and  of  a  dozen  other  elements 
in  varying  proportions.  They  form  colloidal  complexes,  or 
"micelles,"  of  which  the  constitution  and  intimate  structure 
are  unknown. 

All  that  one  does  know  at  the  present  time  on  this  point 
is  that  living  albuminous  "micelles''  are  complexes  main- 
taining themselves  at  a  certain  constant  state  of  physico- 
chemical  equilibrium,  by  drawing  from  their  surrounding 
medium  the  substances  of  which  they  are  composed  and 
which  they  assimilate;  and  by  eliminating  the  useless  waste 


THEORIES  OP  IMMUNITY  ISO 

from  these  transformating  reactions,  and  by  utilizing  other 
substances  the  transformations  of  which  furnish  the  energy 
needed  for  the  work  so  performed. 

An  albuminous  "micelle"  thus  may  be  compared  to  a 
moving  engine,  which,  thanks  to  special  affinities,  draws 
from  the  medium  through  which  it  passes  the  fuel  necessary 
to  produce  its  working  energy,  and  at  the  same  time  matter 
identical  to  its  own  in  order  to  keep  its  parts  in  good  repair 
and  even  to  strengthen  them. 

Albuminous  "micelles"  are  the  nutritive  units  of  living 
matter,  and  all  "micelles"  of  similar  albumin  have  the  same 
physicochemical  equilibrium.  "Micelles"  of  different  albu- 
mins are  distinguished  among  each  other  by  differences  in 
physicochemical  equilibrium  and  it  has  been  determined 
that  the  albumins  of  all  beings  belonging  to  the  same  plant  or 
animal  species  are  the  same. 

The  albumins  of  different  species  have  a  different  physico- 
chemical  equilibrium.  Thus  the  white  of  egg  from  a  hen 
has  not  the  same  properties  as  the  white  of  egg  from  other 
birds,  the  casein  of  cow's  milk  is  different  from  that  of  goat's 
milk;  the  blood,  the  muscular  or  nervous  substances  of  the 
horse  are  different  from  the  same  substances  fi;om  all  other 
animals;  whereas  the  salts  and  the  crystalloids  entering  into 
the  composition  of  the  tissues  of  different  plants  and  animals 
and  which  are  derived  from  the  albumins  are  always  identical. 

The  specific  differences  between  the  "micelles"  and  the 
albumins  which  they  form  are  therefore  determined  solely 
by  differences  in  the  proportions  of  the  component  elements, 
by  the  arrangement  of  these  elements  and  by  the  different 
physicochemical  equilibria  resulting. 

We  do  not  know  of  any  living  being  that  might  be  con- 
stituted by  a  single  free  albuminous  "micelle." 

The  biological  unit  of  living  matter  is  a  cell,  and  a  cell  is 
an  arrangement  of  a  certain  number  of  albuminous  "micelles" 
of  different  structures,  physicochemical  equilibria  and  there- 
fore functions  which  form  a  harmonious  structural  and 
functional  whole. 

At  least  three  kinds  of  "micelles"  can  be  distinguished  in 
a  cell :  those  forming  the  plasma,  the  nucleus  and  the  external 


190  THEORETICAL  DEDUCTIONS 

membrane.  All  these  particles  form  more  or  less  dense 
agglomerations,  are  immersed  in  a  clear  liquid  composed  of 
salts  and  crystalloids.  The  cells  themselves  are  immersed 
in  a  liquid  which  is  composed  of  the  same  salts  and  crystal- 
loids, and  which  in  addition  contains  colloidal  particles 
(plasma,  lymph,  etc.). 

From  the  point  of  view  of  the  nutrition  of  intracellular 
particles,  we  distinguish  in  the  organism  three  zones  or  media 
through  which  nutritive  substances  must  pass. 

These  zones  or  media  are  separated  from  each  other  by 
dialysing  membranes  which  function  by  virtue  of  their 
density,  and  by  virtue  of  the  differences  in  tonicity  of  the 
liquids  on  either  side  of  the  membrane,  and  especially  by 
virtue  of  the  chemical  affinities  between  the  components  of 
the  membrane  and  of  these  liquids. 

The  organism  as  a  whole  begins  by  making  a  first  choice 
of  the  substances  needed  for  its  nutrition  from  the  first 
external  medium.  A  second  choice  is  made  by  the  mem- 
branes of  the  digestive  tract  which  allow  to  pass  into  the 
blood  only  certain  selected  substances  which  have  been 
transformed  into  simple  compounds.  A  third  choice  is  made 
by  the  cell-membranes  which  absorb  certain  substances 
and  allow  the  remainder  to  be  eliminated  by  the  kidneys 
and  the  intestines. 

In  this  way,  the  alimentary  substances  absorbed  by  the 
mouth  undergo  a  series  of  successive  fragmentations  and 
selective  passages  through  the  membranes  before  they,  in  a 
crystalloid  state,  reach  the  intracellular  "micelles,"  that 
is  the  nutrition  units. 

A  cell  may  allow  certain  colloids  made  up  of  small  "micelles" 
to  penetrate  into  its  interior.  If  these  "micelles"  are  homo- 
geneous, that  is  to  say,  have  the  same  physico-chemical  equili- 
brium as  those  which  compose  the  plasma  of  the  cell,  the 
cell  may  assimilate  a  certain  number  without  undergoing 
appreciable  change  in  its  own  gejneral  nutritive  equilibrium; 
but  in  the  case  of  "micelles"  having  physico-chemical  equili- 
bria differing  from  those  of  the  cell  "micelles,"  the  nutrition 
equilibrium  of  the  invaded  cell  and  of  the  new  "micelles" 
will  be  disturbed  to  a  greater  or  less  extent. 


THEORIES  OF  IMMUNITY  191 

All  albuminous  micelle,  considered  as  a  unit  of  specific 
function  can  no  more  assimilate  entire  ''micelles,"  whether 
homogeneous  or  specifically  different  than  a  house  or  a 
machine  could  be  constructed  from  other  complete  houses 
or  machines. 

In  either  case,  the  first  step  must  be  to  demolish,  isolate 
and  separate  the  individual  materials,  which  will  then  possess 
no  specificity  and  with  which  new  units  can  be  reconstructed 
according  to  the  plans  and  specifications. 

The  differentiated  superior  organism  is  guided  in  its  choice 
of  food  by  its  organs  of  sensation  and  by  its  intelligence; 
the  second  and  third  degree  units  are  guided  by  positive 
or  negative  chemotaxis  which  is  but  the  non-differentiated 
combination  of  feeling  and  intelligence;  and  it  is  likewise 
affinities  or  chemotaxis  which  determine  the  formation  of 
antibodies  as  well  as  the  action  of  these  latter  on  their 
antigens. 

In  order  to  well  understand  the  mechanism  of  the  results 
which  these  reactions  may  have  for  the  entire  organism,  we 
must  always  remember  that: 

1.  The  work  of  demolition  or  of  digestion  for  each  nutritive 
unit  must  take  place  outside  of  its  interior.  The  particle, 
the  cell,  and  the  entire  organism,  expel  from  their  interior 
beyond  their  protecting  membranes,  the  substances  (anti- 
bodies) or,  more  generally  speaking  the  energy  which  is 
needed  for  the  digestion  or  transformation  of  foreign  sub- 
stances (antigens).  This  is  done  by  that  chemotaxis  which 
by  sensation,  intelligence  and  memory  can  act  at  a  distance. 
Thus  it  is  that  the  sight  of  food  causes  the  sensation  of  appe- 
tite and  the  secretion  of  gastric  juice,  and  that  the  sight  or 
odor  of  individuals  of  opposite  yex  causes  amorous  feelings 
and  corresponding  reactions  of  the  reproductive  organs. 

2.  In  differentiated  organisms  each  functional  unit,  while 
its  reactions  obey  its  own  chemotaxis,  must  also  conform 
to  the  chemotaxis  of  the  whole.  The  "micelle"  is  influenced 
by  the  chemotaxis  of  the  whole  cell,  the  cell  by  the  chemo- 
taxis of  the  organism,  the  organism  by  the  surroundings  and 
the  society  in  which  it  lives,  and  so  on;  and  the  history  of 
the  greatest  organization  of  units,  the  society  of  nations  is 


192  THEORETICAL  DEDUCTIONS 

reechoed  inversely  by  the  same  routes  back  again  to  the 
"micelles." 

In  order  to  understand  in  its  entirety,  the  mechanism  by 
which  the  animal  organism  can  live  normally,  become  ill  and 
recover,  we  must  also  take  into  account  the  fact  that  the 
individual  reactions  of  "micelles"  and  of  cells,  determined 
by  specific  chemotaxis  are  influenced  also  by  the  reactions 
of  the  central  nervous  system  which  dominates  the  functions 
of  all  the  units  of  the  organism,  and  can  by  itself  disturb  or 
readjust  the  nutritive  equilibrium  of  these  units. 

It  is  always  the  central  nervous  system  which,  in  the  last 
resort,  reestablishes  normal  equilibrium ;  or,  more  accurately, 
which  establishes  a  neiv  general  equilihrimn  in  an  organism 
which  has  been  influenced  more  or  less  seriously  by  a  hetero- 
geneous substance;  and  the  influence  of  the  central  nervous 
system  will  be  all  the  greater,  as  it  will  have  attained  a  higher 
degree  of  development. 

All  these  considerations  lead  us  to  conclude  therefore  that 
an  organism  is  absolutely  incapable  of  assimilating  colloid 
particles  wHich  are  specifically  dift'erent  from  its  own  without 
digesting  them.  This  results  not  from  a  defensive  biological 
law,  but  simply  from  the  physicochemical  properties  of  its 
structural  and  functional  units. 

This  having  been  stated,  the  theory  of  immunity  and  of 
anaphylaxis  may  be  formulated  as  follows : 

Every  bacterium,  every  substance  which  penetrates  in  a 
colloid  state,  into  the  blood  or  the  tissues,  or  in  other  words, 
into  the  interior  of  an  animal  organism  must  be  transformed 
into  salts  and  crystalloids,  that  is,  must  be  digested  in  order 
to  be  assimilated  or  eliminated. 

Every  organism,  by  its  cells,  glands  or  organs  normally 
produces  a  certain  quantity  of  the  substance,  or  more  exactly 
of  a  series  of  substances  which  carry  on  this  digestion. 

When  an  organism  has  once  been  obliged  to  perform  this 
operation,  it  continues  to  produce  digestive  substances  in 
quantity  greater  than  normal.  It  is  then  immunized  and 
anaphylactized. 

All  the  substances  which  the  organism  is  obliged  to  digest 
in  its  interior  are  antigens. 


THEORIES  OF  IMMUNITY  193 

The  digestive  substances  normally  produced  by  the  organ- 
ism are  normal  antibodies. 

The  excess  antibody  found  in  the  blood  and  in  the  fluids 
of  an  immunized  anaphylactized  organism,  is  the  excess  of 
one  of  the  digestive  substances  of  which  the  whole  constitutes 
the  normal  antibody.  The  excess  antibody  found  in  the 
serum  of  immunized  animals  is  a  substance  which  contributes 
to  the  digestion  of  the  corresponding  antigen,  without  being 
able  in  itself  to  finish  this  operation. 

Reactions  between  antibodies  and  antigens  are  specific, 
but  are  not  always  exclusively  so. 

Thanks  to  the  antibodies  in  excess,  the  organism  will 
digest  more  easily  and  more  rapidly  antigens  which  have 
determined  the  excess  of  these  antibodies  and  the  results 
will  be : 

1.  A  certain  degree  of  anti-infectious  or  antitoxic  immunity 
in  those  cases  where  the  antigen  is  a  germ  which  is  patho- 
genic by  its  albumin  or  by  its  toxin. 

2.  A  certain  chronic  morbid  state  determined  by  the 
functional  insufficiency  of  the  organs  assigned  to  the  pro- 
duction of  the  excess  antibodies,  and  lasting  as  long  as  the 
overproduction  of  the  antibodies. 

3.  Anaphylactic  crises  more  or  less  acute  and  serious, 
whenever  a  new  and  sufficient  dose  of  antigen  will  suddenly 
combine  with  the  excess  antibody  and  form  a  precipitate. 

Thus  acquired  anti-infectious  immunity  consists  in  the 
ability  to  digest  a  certain  dose  of  infectious  germs  before 
these  germs  have  had  time  to  multiply  so  as  to  become  patho- 
genic; and  the  organism  acquires  this  property  by  producing 
a  series  of  intracellular  and  extracellular  digestive  ferments. 
One  of  these  ferments  is  the  excess  antibody. 

The  first  phase  of  this  digestion,  that  is,  the  combination 
between  the  antigen  and  the  excess  antibody,  occurs  there- 
fore outside  the  cells,  in  the  fluids  of  the  organism.  If  the 
quantity  as  well  as  the  quality  of  the  antigen  is  such  as  to 
form  an  abundant  precipitate  with  the  antibody,  the  defen- 
sive act  of  the  organism,  the  neutralization  of  the  infectious 
agent,  will  be  accompanied  by  pathologic  manifestations 
which  constitute  the  anaphylactic  crisis. 


194  THEORETICAL  DEDUCTIONS 

The  mechanism  of  anti-  or  tachyphylaxis  must  therefore 
be  considered  and  explained  in  two  different  ways: 

1.  As  a  specific  neutralization  of  the  antigen  by  the  excess 
antibody. 

2.  As  a  reflex  reaction  of  the  nervous  centers  on  the  intra- 
cellular metabolism  caused  by  the  selective  action  of  certain 
antigens  on  the  nerve  centers  regulating  cellular  nutrition. 
In  this  case,  the  reciprocal  specificity  of  antigens  and  anti- 
bodies does  not  come  into  play,  or  plays  only  a  secondary 
role. 


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